Benzimidazole derivatives and use thereof

ABSTRACT

The invention provides compounds that are useful as sodium channel blockers. In one aspect, the invention provides compounds of Formula I: 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts, solvates, hydrates, or diastereomers thereof, wherein W 1 , W 2 , W 3 , W 4 , U, G, m, R 1 , and R 2  are defined in the disclosure. In certain embodiments, the invention provides compounds of Formulae II to V as set forth supra. The invention also provides the use of compounds of any of the above discussed formulae to treat a disorder responsive to blockade of sodium channels. In one embodiment, Compounds of the Invention are useful for treating pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 61/901,507, filed Nov. 8, 2013. The content of the afore-mentionedpatent application is incorporated herein by its entirety.

BACKGROUND OF THE INVENTION

Voltage-gated sodium channels (VGSCs) are found in all excitable cells.In neuronal cells of the central nervous system (CNS) and peripheralnervous system (PNS) sodium channels are primarily responsible forgenerating the rapid upstroke of the action potential. In this mannersodium channels are essential to the initiation and propagation ofelectrical signals in the nervous system. Proper function of sodiumchannels is therefore necessary for normal function of the neuron.Consequently, aberrant sodium channel function is thought to underlie avariety of medical disorders (See Hubner et al., Hum. Mol. Genet.11:2435-2445 (2002) for a general review of inherited ion channeldisorders) including epilepsy (Yogeeswari et al, Curr. Drug Target5:589-602 (2004)), arrhythmia (Noble, Proc. Natl. Acad. Sci. USA99:5755-5756 (2002)), myotonia (Cannon, Kidney Int. 57:772-779 (2000)),and pain (Wood et al., J. Neurobiol., 61:55-71 (2004)).

VGSCs are composed of one α-subunit, which forms the core of the channeland is responsible for voltage-dependent gating and ion permeation, andseveral auxiliary β-subunits (see, e.g., Chahine et al., CNS &Neurological Disorders-Drug Targets 7:144-158 (2008) and Kyle and Ilyin,J. Med. Chem. 50:2583-2588 (2007)). α-Subunits are large proteinscomposed of four homologous domains. Each domain contains six α-helicaltransmembrane spanning segments. There are currently nine known membersof the family of voltage-gated sodium channel α-subunits. Names for thisfamily include SCNx, SCNAx, and Na_(v)x.x (see Table 1, below). The VGSCfamily has been phylogenetically divided into two subfamilies Na_(v)1.x(all but SCN6A) and Na_(v)2.x (SCN6A). The Na_(v)1.x subfamily can befunctionally subdivided into two groups, those which are sensitive toblocking by tetrodotoxin (TTX-sensitive or TTX-s) and those which areresistant to blocking by tetrodotoxin (TTX-resistant or TTX-r).

There are three members of the subgroup of TTX-resistant sodiumchannels. The SCN5A gene product (Na_(v)1.5, Hl) is almost exclusivelyexpressed in cardiac tissue and has been shown to underlie a variety ofcardiac arrhythmias and other conduction disorders (Liu et al., Am. J.Pharmacogenomics 3:173-179 (2003)). Consequently, blockers of Na_(v)1.5have found clinical utility in treatment of such disorders (Srivatsa etal., Curr. Cardiol. Rep. 4:401-410 (2002)). The remaining TTX-resistantsodium channels, Na_(v)1.8 (SCN10A, PN3, SNS) and Na_(v)1.9 (SCN11A,NaN, SNS2) are expressed in the peripheral nervous system and showpreferential expression in primary nociceptive neurons. Human geneticvariants of these channels have not been associated with any inheritedclinical disorder. However, aberrant expression of Na_(v)1.8 has beenfound in the CNS of human multiple sclerosis (MS) patients and also in arodent model of MS (Black et al., Proc. Natl. Acad. Sci. USA97:11598-115602 (2000)). Evidence for involvement in nociception is bothassociative (preferential expression in nociceptive neurons) and direct(genetic knockout). Na_(v)1.8-null mice exhibited typical nociceptivebehavior in response to acute noxious stimulation but had significantdeficits in referred pain and hyperalgesia (Laird et al., J. Neurosci.22:8352-8356 (2002)).

TABLE 1 Voltage-gated sodium channel gene family Tissue TTX Disease GeneDistri- IC₅₀ Associ- Type Symbol bution (nM) ation Indications Na_(v)1.1SCN1A CNS/PNS 10 Epilepsy Pain, seizures, neurodegen- eration Na_(v)1.2SCN2A CNS 10 Epilepsy Epilepsy, neurodegen- eration Na_(v)1.3 SCN3A CNS15 — Pain Na_(v)1.4 SCN4A Skeletal 25 Myotonia Myotonia muscle Na_(v)1.5SCN5A Heart 2,000 Arrhythmia Arrhythmia muscle Na_(v)1.6 SCN8A CNS/PNS 6— Pain, movement disorders Na_(v)1.7 SCN9A PNS 25 Eryther- Pain malgiaNa_(v)1.8 SCN10A PNS 50,000 — Pain Na_(v)1.9 SCN11A PNS 1,000 — Pain

The Na_(v)1.7 (PN1, SCN9A) VGSC is sensitive to blocking by tetrodotoxinand is preferentially expressed in peripheral sympathetic and sensoryneurons. The SCN9A gene has been cloned from a number of species,including human, rat, and rabbit and shows ˜90% amino acid identitybetween the human and rat genes (Toledo-Aral et al., Proc. Natl. Acad.Sci. USA 94:1527-1532 (1997)).

An increasing body of evidence suggests that Na_(v)1.7 plays a key rolein various pain states, including acute, inflammatory and/or neuropathicpain. Deletion of the SCN9A gene in nociceptive neurons of mice led toan increase in mechanical and thermal pain thresholds and reduction orabolition of inflammatory pain responses (Nassar et al., Proc Natl.Acad. Sci. USA 101:12706-12711 (2004)).

Sodium channel-blocking agents have been reported to be effective in thetreatment of various disease states, and have found particular use aslocal anesthetics, e.g., lidocaine and bupivacaine, and in the treatmentof cardiac arrhythmias, e.g., propafenone and amiodarone, and epilepsy,e.g., lamotrigine, phenyloin and carbamazepine (see Clare et al., DrugDiscovery Today 5:506-510 (2000); Lai et al., Annu. Rev. Pharmacol.Toxicol. 44:371-397 (2004); Anger et al., J. Med. Chem. 44:115-137(2001), and Catterall, Trends Pharmacol. Sci. 8:57-65 (1987)). Each ofthese agents is believed to act by interfering with the rapid influx ofsodium ions.

Other sodium channel blockers such as BW619C89 and lifarizine have beenshown to be neuroprotective in animal models of global and focalischemia (Graham et al., J. Pharmacol. Exp. Ther. 269:854-859 (1994);Brown et al., British J. Pharmacol. 115:1425-1432 (1995)).

It has also been reported that sodium channel-blocking agents can beuseful in the treatment of pain, including acute, chronic, inflammatory,neuropathic, and other types of pain such as rectal, ocular, andsubmandibular pain typically associated with paroxysmal extreme paindisorder; see, for example, Kyle and Ilyin., J. Med. Chem. 50:2583-2588(2007); Wood et al., J. Neurobiol. 61:55-71 (2004); Baker et al., TRENDSin Pharmacological Sciences 22:27-31 (2001); and Lai et al., CurrentOpinion in Neurobiology 13:291-297 (2003); the treatment of neurologicaldisorders such as epilepsy, seizures, epilepsy with febrile seizures,epilepsy with benign familial neonatal infantile seizures, inheritedpain disorders, e.g., primary erthermalgia and paroxysmal extreme paindisorder, familial hemiplegic migraine, and movement disorder; and thetreatment of other psychiatric disorders such as autism, cerebellaratrophy, ataxia, and mental retardation; see, for example, Chahine etal., CNS & Neurological Disorders-Drug Targets 7:144-158 (2008) andMeister and Kearney, J. Clin. Invest. 5:2010-2017 (2005). In addition tothe above-mentioned clinical uses, carbamazepine, lidocaine andphenyloin are used to treat neuropathic pain, such as from trigeminalneuralgia, diabetic neuropathy and other forms of nerve damage (Taylorand Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)). Furthermore,based on a number of similarities between chronic pain and tinnitus,(Moller, Am. J. Otol. 18:577-585 (1997); Tonndorf, Hear. Res. 28:271-275(1987)) it has been proposed that tinnitus should be viewed as a form ofchronic pain sensation (Simpson, et al., Tip. 20:12-18 (1999)). Indeed,lidocaine and carbamazepine have been shown to be efficacious intreating tinnitus (Majumdar, B. et al., Clin. Otolaryngol. 8:175-180(1983); Donaldson, Laryngol. Otol. 95:947-951 (1981)).

Many patients with either acute or chronic pain disorders respond poorlyto current pain therapies, and the development of resistance orinsensitivity to opiates is common. In addition, many of the currentlyavailable treatments have undesirable side effects.

In view of the limited efficacy and/or unacceptable side-effects of thecurrently available agents, there is a pressing need for more effectiveand safer analgesics that work by blocking sodium channels.

SUMMARY OF THE INVENTION

The invention provides compounds that are useful as blockers of sodium(Na⁺) channels. In one aspect, the invention provides compounds asrepresented by the formulae infra., and the pharmaceutically acceptablesalts, solvates, hydrates, and diastereomers thereof (also referred toherein as “the Compounds of the Invention”). In certain embodiments, theCompounds of the Invention can act as blockers of sodium (Na⁺) channels.

In one aspect, the invention provides novel compounds of any one ofFormulae I to V as set forth below, and the pharmaceutically acceptablesalts, solvates, hydrates, and diastereomers thereof.

The invention also provides a method of treating a disorder responsiveto the blockade of sodium channels in a mammal suffering from excessactivity of said channels by administering an effective amount of aCompound of the Invention as described herein.

A further aspect of the invention is to provide a method for treatingpain (e.g., acute pain, chronic pain, which includes but is not limitedto, neuropathic pain, postoperative pain, and inflammatory pain, orsurgical pain) by administering an effective amount of a Compound of theInvention to a mammal in need of such treatment. In a certainembodiment, the invention provides a method for preemptive or palliativetreatment of pain by administering an effective amount of a Compound ofthe Invention to a mammal in need of such treatment.

A further aspect of the invention is to provide a method for treatingstroke, neuronal damage resulting from head trauma, epilepsy, seizures,general epilepsy with febrile seizures, severe myoclonic epilepsy ininfancy, neuronal loss following global and focal ischemia, migraine,familial primary erythromelalgia, paroxysmal extreme pain disorder,cerebellar atrophy, ataxia, dystonia, tremor, mental retardation,autism, a neurodegenerative disorder (e.g., Alzheimer's disease,amyotrophic lateral sclerosis (ALS), or Parkinson's disease), manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia, by administering an effectiveamount of a Compound of the Invention to a mammal in need of suchtreatment.

A further aspect of the invention provides a pharmaceutical compositionuseful for treating a disorder responsive to blockade of sodium ionchannels, said pharmaceutical composition containing an effective amountof a Compound of the Invention in a mixture with one or morepharmaceutically acceptable diluent and/or carriers.

Also, an aspect of the invention provides a method of modulating sodiumchannels in a mammal, wherein said method comprises administering to themammal an effective amount of at least one Compound of the Invention.

In another aspect, the invention relates to the use of the compounds ofthe formulae provided infra. and their pharmaceutically acceptablesalts, diastereomers, hydrates, and solvates, as blockers of sodiumchannels.

A further aspect of the invention provides a Compound of the Inventionfor use in treating pain in a mammal, e.g., acute pain, chronic pain,which includes but is not limited to, neuropathic pain, postoperativepain, and inflammatory pain, or surgical pain.

Yet another aspect of the invention provides a Compound of the Inventionfor use in treating stroke, neuronal damage resulting from head trauma,epilepsy, seizures, general epilepsy with febrile seizures, severemyoclonic epilepsy in infancy, neuronal loss following global and focalischemia, migraine, familial primary erythromelalgia, paroxysmal extremepain disorder, cerebellar atrophy, ataxia, dystonia, tremor, mentalretardation, autism, a neurodegenerative disorder (e.g., Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease),manic depression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia, in a mammal.

Still another aspect of the invention provides radiolabeled Compounds ofthe Invention and the use of such compounds as radioligands in anyappropriately selected competitive binding assays and screeningmethodologies. Thus, the invention further provides a method forscreening a candidate compound for its ability to bind to a sodiumchannel or sodium channel subunit using a radiolabeled Compound of theInvention.

In certain embodiments, the compound is radiolabeled with ³H, ¹¹C, or¹⁴C. This competitive binding assay can be conducted using anyappropriately selected methodology. In one embodiment, the screeningmethod comprises: i) introducing a fixed concentration of theradiolabeled compound to an in vitro preparation comprising a soluble ormembrane-associated sodium channel, subunit or fragment under conditionsthat permit the radiolabeled compound to bind to the channel, subunit orfragment, respectively, to form a conjugate; ii) titrating the conjugatewith a candidate compound; and iii) determining the ability of thecandidate compound to displace the radiolabeled compound from saidchannel, subunit or fragment.

A further aspect of the invention provides the use of a Compound of theInvention in the manufacture of a medicament for treating pain in amammal. In one embodiment, the invention provides the use of a Compoundof the Invention in the manufacture of a medicament for palliative orpreemptive treatment of pain, such as acute pain, chronic pain, orsurgical pain.

In another aspect, the invention provides the use of a Compound of theInvention in the manufacture of a medicament for treating stroke,neuronal damage resulting from head trauma, epilepsy, seizures, generalepilepsy with febrile seizures, severe myoclonic epilepsy in infancy,neuronal loss following global and focal ischemia, migraine, familialprimary erythromelalgia, paroxysmal extreme pain disorder, cerebellaratrophy, ataxia, dystonia, tremor, mental retardation, autism, aneurodegenerative disorder (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS), or Parkinson's disease), manic depression,tinnitus, myotonia, a movement disorder, or cardiac arrhythmia, orproviding local anesthesia, in a mammal.

Additional embodiments and advantages of the invention will be set forthin part in the description that follows, and will flow from thedescription, or can be learned by practice of the invention. Theembodiments and advantages of the invention will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only and are notrestrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Before a further description of the invention, and in order that theinvention may be more readily understood, certain terms are firstdefined and collected herein for convenience.

As used herein, the term “alkyl” by itself or as part of another grouprefers to a straight- or branched-chain aliphatic hydrocarbon containingone to twelve (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbonatoms (i.e., C₁₋₁₂ alkyl) or the number of carbon atoms designated(i.e., a C₁ alkyl such as methyl, a C₂ alkyl such as ethyl, a C₃ alkylsuch as propyl or isopropyl, etc.). For convenience, the term “alkyl” asused herein also includes an alkanediyl functional group, for example,an alkyl group that has two points of connection, such as, —CH₂— and—CH₂CH₂—. Nevertheless, the term “alkyl” as used in the presentdisclosure does not expressly include unsaturated aliphatic hydrocarbonchains (e.g., alkenyl and alkynyl groups). In addition, the term “C₀alkyl” as used herein refers to a bond (i.e., absent) or H.

In one embodiment, the alkyl group is chosen from a straight chain C₁₋₁₀alkyl group. In another embodiment, the alkyl group is chosen from abranched chain C₁₋₁₀ alkyl group. In another embodiment, the alkyl groupis chosen from a straight chain C₁₋₆ alkyl group. In another embodiment,the alkyl group is chosen from a branched chain C₃₋₆ alkyl group. Inanother embodiment, the alkyl group is chosen from a straight chain C₁₋₄alkyl group. In another embodiment, the alkyl group is chosen from astraight chain C₂₋₄ alkyl group. In another embodiment, the alkyl groupis chosen from a branched chain C₃₋₄ alkyl group. Non-limiting exemplaryalkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl, -iso-propyl, -sec-butyl, -iso-butyl,-tert-butyl, -iso-pentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl,2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl,4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl,1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl,1,2-dimethylheptyl, 1,3-dimethylheptyl, and 3,3-dimethylheptyl and thelike. Non-limiting exemplary C₁₋₄ alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.

For the purpose of the disclosure, the term “optionally substitutedalkyl” as used by itself or as part of another group means that thealkyl as defined above is either unsubstituted or substituted with oneor more substituents independently chosen from amide, (amido)alkyl,hydroxyl, carboxy, alkoxy, ureido, nitro, halogen, alkyl, alkylcarbonyl,alkylsulfonyl, arylsulfonyl, sulfonamide, guanidino, carboxyalkyl,cycloalkyl, heterocyclyl, heteroaryl, haloalkoxy, aryloxy, aralkyloxy,alkylthio, arylcarbonyl, and the like. In one embodiment, the optionallysubstituted alkyl is substituted with two substituents. In anotherembodiment, the optionally substituted alkyl is substituted with onesubstituent. Non-limiting exemplary optionally substituted alkyl groupsinclude —CH₂CH₂NO₂, —CH₂CH₂CO₂H, —CH₂CH₂SO₂CH₃, —CH₂CH₂COPh, and thelike.

As used herein, the term “cycloalkyl” by itself or as part of anothergroup refers to saturated, partially unsaturated (e.g. cycloalkenyl thatcontains one or two double bonds), and partially-oxidized (e.g.,containing a carbon atom out of a carbonyl group as a ring buildingblock) cyclic aliphatic hydrocarbons containing one to three rings withor without the number of carbons designated. In certain embodiments, theterm “cycloalkyl” as used herein has from three to twelve carbon atoms(i.e., C₃₋₁₂ cycloalkyl). In one embodiment, the cycloalkyl group issaturated. In another embodiment, the cycloalkyl group is unsaturated.In still another embodiment, the cycloalkyl group is oxidized (e.g., acyclohexanone group).

In one embodiment, the cycloalkyl group has two-fused rings. In oneembodiment, the cycloalkyl group has one ring. In another embodiment,the cycloalkyl group is chosen from a C₃₋₈ cycloalkyl group. In anotherembodiment, the cycloalkyl group is chosen from a C₄₋₈ cycloalkyl group.In another embodiment, the cycloalkyl group is chosen from a C₃₋₆cycloalkyl group. Non-limiting exemplary cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, and the like.

The term “optionally substituted cycloalkyl” as used by itself or aspart of another group means that the cycloalkyl as defined above iseither unsubstituted or substituted with or more substituentsindependently chosen from halo, nitro, cyano, hydroxy, amino,alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, dihydroxyalkyl,alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido,sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl,ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, alkoxyalkyl, (amino)alkyl,hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclyl)alkyl,(heteroaryl)alkyl, and the like.

In certain embodiments, the optionally substituted cycloalkyl issubstituted with one to three substituents. As illustration,non-limiting exemplary optionally substituted cycloalkyl groups include:

The term “cycloalkenyl” as used by itself or part of another grouprefers to a cycloalkyl group as defined above containing one, two, orthree carbon-to-carbon double bonds. In one embodiment, the cycloalkenylhas one carbon-to-carbon double bond. In another embodiment, thecycloalkenyl group is chosen from a C₄₋₈ cycloalkenyl group. Exemplarycycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, and thelike.

The term “alkenyl” as used by itself or as part of another group refersto an alkyl group as defined above containing one, two or threecarbon-to-carbon double bonds. In one embodiment, the alkenyl group ischosen from a C₂₋₆ alkenyl group. In another embodiment, the alkenylgroup is chosen from a C₂₋₄ alkenyl group. Non-limiting exemplaryalkenyl groups include ethenyl, propenyl, isopropenyl, butenyl,sec-butenyl,-iso-butylenyl, -1-pentenyl, -2-pentenyl,-3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl,-1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl,-3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl,-3-nonenyl, -1-decenyl, -2-decenyl, -3-decenyl, and the like.

The term “alkynyl” as used by itself or as part of another group refersto an alkyl group as defined above containing one to threecarbon-to-carbon triple bonds. In one embodiment, the alkynyl has onecarbon-to-carbon triple bond. In one embodiment, the alkynyl group ischosen from a C₂₋₆ alkynyl group. In another embodiment, the alkynylgroup is chosen from a C₂₋₄ alkynyl group. Non-limiting exemplaryalkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl,-1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl,-2-hexynyl, 3-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl,-6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl,-8-nonynyl, -1-decynyl, -2-decynyl, -9-decynyl, and the like.

The term “haloalkyl” as used by itself or as part of another grouprefers to an alkyl group as defined above substituted by one or morefluorine, chlorine, bromine and/or iodine atoms. In one embodiment, thealkyl group is substituted by one, two, or three fluorine and/orchlorine atoms. In another embodiment, the haloalkyl group is chosenfrom a C₁₋₄ haloalkyl group. Non-limiting exemplary haloalkyl groupsinclude fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl,1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.

The term “hydroxyalkyl” as used by itself or as part of another grouprefers to an alkyl group as defined above substituted with a hydroxylgroup (i.e., —OH).

As used herein, the term “alkoxy” by itself or as part of another grouprefers to an optionally substituted alkyl as above defined, anoptionally substituted cycloalkyl as above defined, an optionallysubstituted heterocyclyl (defined infra.), an optionally substitutedaryl (defined infra.), or an optionally substituted heteroaryl (definedinfra.) that is attached to an oxygen atom, i.e., —OR^(c) (wherein R^(c)is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which isoptionally substituted). Exemplified alkoxy groups include methoxy,ethoxy, tert-butoxy, cyclohexanoxy, and the like.

For the purpose of this disclosure, the term “—S-alkyl” or “alkylthio”as used by itself or as part of another group refers to a sulfur atomsubstituted by an optionally substituted alkyl group as above defined.Non-limiting exemplary —S-alkyl or alkylthio groups include —SCH₃, and—SCH₂CH₃.

The term “alkoxyalkyl” as used herein by itself or as part of anothergroup refers to any of the above-mentioned alkyl groups substituted withany of the above-mentioned alkoxy groups. Non-limiting exemplaryalkoxyalkyl groups include, but are not limited to, methoxymethyl,methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl,ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl,propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl,isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.

The term “haloalkoxy” as used herein by itself or as part of anothergroup refers to an alkoxy group as above defined that is substituted byone or more same or different halogen atoms (i.e., fluorine, chlorine,bromine and iodine atoms). Non-limiting exemplary haloalkoxy groupsinclude fluoromethoxy, difluoromethoxy, trifluoromethoxy, and2,2,2-trifluoroethoxy.

As used herein, the term “aryl” by itself or as part of another grouprefers to a monocyclic or bicyclic aromatic ring system having from sixto fourteen carbon atoms (i.e., C₆-C₁₄ aryl). Non-limiting exemplaryaryl groups include phenyl (abbreviated as “Ph”), naphthyl, phenanthryl,anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenylgroups.

The term “optionally substituted aryl” as used herein by itself or aspart of another group means that the aryl as defined above is eitherunsubstituted or substituted with one to five substituents independentlychosen from halo, nitro, cyano, hydroxy, amino, alkylamino,dialkylamino, haloalkyl, hydroxyalkyl, dihydroxyalkyl, alkoxy,haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido,alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido,guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclyl, alkoxyalkyl, (amino)alkyl,hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclyl)alkyl,(heteroaryl)alkyl, and the like.

In certain embodiments, the optionally substituted aryl is an optionallysubstituted phenyl that has one to five substituents. Non-limitingexemplary substituted aryl groups include 2-methylphenyl,2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl,4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl,3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di-methoxyphenyl,3,5-di-fluorophenyl 3,5-di-methylphenyl and 3,5-dimethoxy,4-methylphenyl, 2-fluoro-3-chlorophenyl,2-cyano-3-trifluoromethylphenyl, 2-trifluoromethyl-3-cyanophenyl,4-cyanophenyl, 4-trifluoromethylphenyl, and 3-chloro-4-fluorophenyl. Theterm optionally substituted aryl is meant to include groups having fusedoptionally substituted cycloalkyl and fused optionally substitutedheterocyclyl rings. Examples include

The term “aryloxy” as used by itself or as part of another group refersto an optionally substituted aryl attached to a terminal oxygen atom. Anon-limiting exemplary aryloxy group is PhO—.

The term “aralkyloxy” as used by itself or as part of another grouprefers to an aralkyl group attached to a terminal oxygen atom. Anon-limiting exemplary aralkyloxy group is PhCH₂O—.

The term “heteroaryl” or “heteroaromatic” refers to monocyclic andbicyclic aromatic ring systems having 1, 2, 3, or 4 heteroatoms. Incertain embodiments, the heteroatoms are independently selected from thegroup consisting of oxygen, nitrogen, and sulfur. In others embodiments,the heteroaryl is a 5-membered or 6-membered heteroaryl. Non-limitingexemplary heteroaryl groups include thienyl, benzo[b]thienyl,naphthol[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl,isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl,quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl,phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl,thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl,benzimidazolyl, and phenoxazinyl. In one embodiment, the heteroaryl ischosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g.,2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl,and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, andpyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl,pyrimidin-5-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl,thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl,isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl,oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl,isoxazol-4-yl, and isoxazol-5-yl). The term “heteroaryl” is also meantto include possible N-oxides. Exemplary N-oxides include pyridyl N-oxideand the like.

The term “optionally substituted heteroaryl” as used by itself or aspart of another group means that the heteroaryl as defined above iseither unsubstituted or substituted with one to four substituents, e.g.,one or two substituents, independently chosen from halo, nitro, cyano,hydroxy, amino, alkylamino, dialkylamino, haloalkyl, monohydroxyalkyl,dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio,carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl,arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl,(dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl,(heterocyclyl)alkyl, and (heteroaryl)alkyl. In one embodiment, theoptionally substituted heteroaryl has one substituent. In oneembodiment, the optionally substituted is an optionally substitutedpyridyl, i.e., 2-, 3-, or 4-pyridyl. Any available carbon or nitrogenatom can be substituted. In another embodiment, the optionallysubstituted heteroaryl is an optionally substituted indole.

The term “heterocyclyl”, “heterocycle”, or “heterocyclic” as used byitself or as part of another group refers to saturated and partiallyunsaturated (e.g., containing one or two double bonds) cyclic groupscontaining one, two, or three rings having from 3 to 14 ring members andat least one heteroatom. Further, the term “heterocyclyl” or“heterocycle” as used herein is meant to include cyclic groups that arepartially oxidized, for example, 2-imidazolidinone, andpyrrolidin-2-one, etc.

A 3-membered heterocyclyl can contain up to 1 heteroatom, a 4-memberedheterocyclyl can contain up to 2 heteroatoms, a 5-membered heterocyclylcan contain up to 4 heteroatoms, and a 6-membered heterocyclyl cancontain up to 4 heteroatoms, and a 7-membered heterocyclyl can containup to 5 heteroatoms. Each heteroatom is independently selected from thegroup consisting of oxygen, sulfur (including sulfoxide and sulfone),and/or nitrogen atoms that can be quaternized. In certain embodiments,the heterocyclyl or heterocycle group is chosen from a 5- or 6-memberedcyclic group containing one ring and one or two oxygen and/or nitrogenatoms. In another embodiment, the heterocyclyl or heterocycle group ischosen from a 4- to 8-membered heterocycle. In another embodiment, theheterocyclyl or heterocycle group is chosen from a 4- to 12-memberedheterocycle. In another embodiment, the heterocyclyl or heterocyclegroup is chosen from a 3- to 8-membered heterocycle. The heterocyclyl orheterocycle can be optionally linked to the rest of the molecule througha carbon or hetero atom. Non-limiting exemplary heterocyclyl orheterocycle groups include 2-imidazolidinone, piperidinyl, morpholinyl,piperazinyl, and pyrrolidinyl.

The term “optionally substituted heterocyclyl” or “optionallysubstituted heterocycle” as used herein by itself or part of anothergroup means the heterocyclyl or heterocycle as defined above is eitherunsubstituted or substituted with one to five substituents independentlyselected from halo, nitro, cyano, hydroxy, amino, alkylamino,dialkylamino, haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy,haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido,alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido,guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclyl, alkoxyalkyl, (amino)alkyl,hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclyl)alkyl,(heteroaryl)alkyl, and the like. Substitution may occur on any availablecarbon or nitrogen atom. An optionally substituted heterocyclyl orheterocycle can be fused to an aryl group to provide an optionallysubstituted aryl as described above. Non-limiting exemplary optionallysubstituted heterocyclyl or heterocycle groups include:

The term “amino” as used herein by itself or as part of another grouprefers to —NH₂.

The phrase “optionally substituted amino” by itself or as part ofanother group means that the amino as defined above is eitherunsubstituted or substituted with one or two substituents independentlyselected from (amido)alkyl, carboxy, carboxamido, alkyl, alkylcarbonyl,alkylsulfonyl, arylsulfonyl, carboxyalkyl, cycloalkyl, heterocyclyl,heteroaryl, arylcarbonyl, (cycloalkyl)carbonyl, and the like. Each ofthe above amino substituents can be further optionally substituted.

The term “(amino)alkyl” or “aminoalkyl” as used herein by itself or aspart of another group refers to any of the above-mentioned alkyl groupssubstituted with an amino group. Non-limiting exemplary amino alkylgroups include —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂NH₂ andthe like.

The term “alkylamino” or “(alkyl)amino” as used herein by itself or aspart of another group refers to an amino group substituted by an alkylgroup as above mentioned. Non-limiting exemplary alkylamino or(alkyl)amino groups include —NHCH₃, —NHCH₂CH₃, and the like.

The term “dialkylamino” or “(dialkyl)amino” as used herein by itself oras part of another group refers to an amino group substituted by twoalkyl groups as above mentioned, which can be the same or different.Non-limiting exemplary dialkylamino groups include —N(CH₃)₂,—N(CH₃)(CH₂CH₃), and the like.

The “arylamino” as used herein by itself or as part of another grouprefers to an amino group substituted by an aryl group as abovementioned. Non-limiting exemplary dialkylamino groups include —NHPh andthe like.

For the purpose of the present disclosure, the term “cycloalkylamino” asused by itself or as part of another group refers to an amino groupsubstituted by a cycloalkyl group as above mentioned. Non-limitingexemplary cycloalkylamino groups include

and the like.

The term “cyano” by itself or as part of another group stands for a —CNgroup.

As used herein, the term “amide” or “amido” by itself or as part ofanother group refers to a radical having the formula of—C(═O)NR^(a)R^(b) (i.e., —C(O)NR^(a)R^(b)) or —N(R^(a))C(O)—, whereinR^(a) and R^(b) are each independently hydrogen, optionally substitutedalkyl, optionally substituted aryl, or optionally substitutedheteroaryl; or R^(a) and R^(b) taken together with the nitrogen to whichthey are attached form a 3- to 8-membered heterocycle group.Non-limiting exemplary amide or amido groups include —C(O)NH₂,—NHC(O)CH₃, and the like.

The term “carboxamido” by itself or as part of another group refers to aradical of formula —C(═O)NR^(a)R^(b), wherein R^(a) and R^(b) are eachindependently hydrogen, optionally substituted alkyl, optionallysubstituted aryl, or optionally substituted heteroaryl; or R^(a) andR^(b) taken together with the nitrogen to which they are attached form a3- to 8-membered heterocycle group. Non-limiting exemplary carboxamidogroups include —C(O)NH₂, —C(O)N(H)CH₃, —C(O)N(CH₃)₂, and —C(O)N(H)Ph.

The term “(amido)alkyl” by itself or as part of another group refers toan alkyl group that is substituted by an amido group as above defined.Non-limiting exemplary (amido)alkyl groups include —CH₂CONH₂,

and the like.

The term “sulfonamide” or “sulfonamido” as used herein by itself or aspart of another group refers to a radical of the formula—SO₂N(R^(2a)R^(2b)), wherein R^(2a) and R^(2b) are each independentlyhydrogen, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl; or R^(2a) and R^(2b) taken together with the nitrogen towhich they are attached form a 3- to 8-membered heterocyclyl group.Non-limiting exemplary sulfonamido groups include —SO₂NH₂, —SO₂N(H)CH₃,—SO₂N(H)Ph, and the like.

The term “carbonyl” as used by itself or as part of another group refersto —C(═O)— (i.e, —C(O)—).

The term “alkylsulfonyl” as used herein by itself or as part of anothergroup refers to a sulfonyl group, i.e., —SO₂—, substituted by any of theabove-mentioned optionally substituted alkyl groups. A non-limitingexemplary alkylsulfonyl group is —SO₂CH₃.

The term “arylsulfonyl” by itself or as part of another group refers toa sulfonyl group, i.e., —SO₂—, substituted by any of the above-mentionedoptionally substituted aryl groups. A non-limiting exemplaryarylsulfonyl group is —SO₂Ph.

The term “mercaptoalkyl” as used by itself or as part of another grouprefers to any of the above-mentioned alkyl groups substituted by a —SHgroup.

The term “sulfinyl” as used by itself or as part of another group refersto a —S(═O)-group substituted by any of the above-mentioned optionallysubstituted alkyl groups. A non-limiting exemplary alkylsulfinyl groupis —S(═O)CH₃.

The term “carboxy” as used by itself or as part of another group refersto a radical of the formula —COOH.

The term “nitro” as used herein by itself or as part of another grouprefers to a radical of the formula —NO₂.

The term “hydroxy” or “hydroxyl” as used herein by itself or as part ofanother group refers to a radical of the formula —OH.

As used herein, the term “aralkyl” by itself or as part of another grouprefers to any of the above-mentioned alkyl groups substituted with one,two, or three optionally substituted aryl groups. In one embodiment, thearalkyl group is a C₁₋₄ alkyl substituted with one optionallysubstituted aryl group. Non-limiting exemplary aralkyl groups includebenzyl, trityl, and phenethyl.

The term “ureido” as used by itself or as part of another group refersto a radical of the formula —NR^(3a)—C(O)—NR^(3b)R^(3d), wherein R^(3a),R^(3b) and R^(3d), each independently, are hydrogen, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl; or R^(3b) andR^(3d) taken together with the nitrogen to which they are attached forma 4- to 8-membered heterocyclyl group. Non-limiting exemplary ureidogroups include —NH—C(═O)—NH₂ and NH—C(═O)—NHCH₃.

The term “guanidino” as used by itself or as part of another grouprefers to a radical of the formula —NR^(4a)—C(═NR^(4b))—NR^(4c)R^(4d),wherein R^(4a), R^(4c), and R^(4d) are each independently hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl; andR^(4b) is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl,carboxamido, or sulfonamido. Non-limiting exemplary guanidino groupsinclude —NH—C(C═NH)—NH₂, —NH—C(C═NCN)—NH₂, —NH—C(C═NH)—NHCH₃ and thelike.

The term “chiral” refers to molecules which have the property ofnon-superimposability of their mirror image partner, which the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “diastereomer” refers to stereoisomers with two or more centersof dissymmetry and whose structures are not mirror images of each other.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction. An equimolar mixture of two enantiomersis called a “racemic mixture” or a “racemate”.

The term “modulate” refers to increasing or decreasing in a testparameter in response to exposure to a Compound of the Invention.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The terms “a” and “an” refer to one or more.

The term “treat,” “treating” or “treatment” is meant to encompassadministering to a subject a Compound of the Invention for the purposesof amelioration or cure, including preemptive and palliative treatment.

The term “about,” as used herein in connection with a measured quantity,refers to the normal variations in that measured quantity, as expectedby the skilled artisan making the measurement and exercising a level ofcare commensurate with the objective of measurement and the precision ofthe measuring equipment.

LIST OF ABBREVIATIONS

AcOH acetic acid

aq. aqueous

° C. degrees Celcius

DCM dichloromethane

DIPEA diisopropylethylamine

DMF dimethylformamide

DMSO dimethylsulfoxide

EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide)

EtOAc ethyl acetate

EtOH ethanol

h hour(s)

HOBt hydroxybenzotriazole

MeOH methanol

Pd/C palladium on carbon

RT room temperature

satd. saturated

Compounds of the Invention

The invention provides compounds as delineated infra. In one embodiment,the Compounds of the Invention act as blockers of Na⁺ channels.Accordingly, these compounds are useful for treating disordersresponsive to blockade of sodium ion channels.

In one aspect, the invention provides a compound of Formula I, or apharmaceutically acceptable salt, solvate, hydrate, or diastereomerthereof:

Wherein

m is 0, 1, 2, 3, 4, 5, or 6;

n is 0, 1, 2, 3, or 4;

Each of W¹, W², W³, and W⁴, independently, is C(R³) or N, provided thatat least one of W¹, W², W³, and W⁴ is C(R³);

G is H, alkyl, alkoxy, amino, amide, aryl, cycloalkyl, R⁶OC(O)—,R⁶C(O)O—, (R⁶)₂NC(O)O—, heterocyclyl, heteroaryl, or sulfonamide,wherein each of the alkyl, alkoxy, amino, amide, aryl, cycloalkyl,heterocyclyl, heteroaryl, R⁶OC(O)—, R⁶C(O)O—, (R⁶)₂NC(O)O—, andsulfonamide is optionally substituted;

U is optionally-substituted naphthyl or

Each of Z¹, Z², Z³, Z⁴, and Z⁵, independently, is CH or N, provided thatat most three of Z¹, Z², Z³, Z⁴, and Z⁵ can be N at the same time;

—Y—X is selected from the group consisting of

-   -   a) —O—(C₀₋₃)alkyl-X, which is optionally substituted;    -   b) —(C₀₋₃)alkyl-S—X, which is optionally substituted;    -   c) —S—(C₁₋₃)alkyl-X, which is optionally substituted;    -   d) —(C₀₋₃)alkyl-S(O)—X, which is optionally substituted;    -   e) —S(O)—(C₁₋₃)alkyl-X, which is optionally substituted;    -   f) —(C₀₋₃)alkyl-S(O)₂—X, which is optionally substituted;    -   g) —S(O)₂—(C₁₋₃)alkyl-X, which is optionally substituted;    -   h) —(C₁₋₃)alkyl-N(R⁵)—X, which is optionally substituted;    -   i) —(C₁₋₃)alkyl-N(R⁵)C(O)—X, which is optionally substituted;    -   j) —(C₁₋₃)alkyl-C(O)N(R⁵)—X, which is optionally substituted;        and    -   l) —(C₁₋₆)alkyl-X, which is optionally substituted;

X is optionally-substituted aryl or optionally-substituted heteroaryl;

E is a bond (i.e., absent) or carbonyl;

R¹ and R², each independently, are H, alkyl, amide, amino, cyano,alkoxy, hydroxyl, halogen, cycloalkyl, aryl, heteroaryl, orheterocyclyl, wherein each of the alkyl, alkoxy, amide, amino,cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionallysubstituted;

R³ and R⁴, each independently, are H, alkyl, alkoxy, amide, amino,R⁶OC(O)—, R⁶C(O)O—, (R⁶)₂NC(O)O—, cyano, cycloalkyl, heterocyclyl,hydroxyl, halogen, sulfonamide, or nitro, wherein each of said alkyl,alkoxy, amide, amino, R⁶OC(O)—, R⁶C(O)O—, (R⁶)₂NC(O)O—, cycloalkyl,heterocyclyl, and sulfonamide groups is optionally substituted;

R⁵, on each occurrence, independently is H, alkyl, cycloalkyl,heterocyclyl, (alkyl)carbonyl, or (amino)carbonyl, wherein each of thealkyl, cycloalkyl, heterocyclyl, (alkyl)carbonyl, and (amino)carbonyl isoptionally substituted; and

R⁶, on each occurrence, independently is H, alkyl, aryl, cycloalkyl,heteroaryl, or heterocyclyl, wherein each of said alkyl, aryl,cycloalkyl, heteroaryl, and heterocyclyl is optionally substituted;

Provided that

-   -   i) when U is

and —Y—X is —O—CH₂—X, then X is further substituted by a group otherthan H;

-   -   ii) when U is

and —Y—X is —O—X, then G is alkoxy, amino, amide, aryl, cycloalkyl,R⁶OC(O)—, R⁶C(O)O—, (R⁶)₂NC(O)O—, heterocyclyl, heteroaryl, orsulfonamide, wherein each of said alkoxy, amino, amide, aryl,cycloalkyl, heterocyclyl, heteroaryl, R⁶OC(O)—, R⁶C(O)O—, (R⁶)₂NC(O)O—,and sulfonamide is optionally substituted; and

-   -   iii) when U is

and —Y—X is —(C₁₋₆)alkyl-X and X is aryl, then said (C₁₋₆)alkyl in —Y—Xis further optionally substituted by (C₁₋₃)alkyl, hydroxyl, halogen,(C₁₋₃)alkoxy, amide, amino, ((C₁₋₃)alkyl)amino, halo (C₁₋₃)alkyl, orhalo(C₁₋₃)alkoxy.

“Optionally-substituted —O—(C₀₋₃)alkyl-X” as used herein means that thealkyl group therein is optionally substituted by one or more (e.g., oneto six) same or different substituents as provided in the definitionsection. Likewise, optionally-substituted “—(C₀₋₃)alkyl-S—X”,optionally-substituted “—S—(C₁₋₃)alkyl-X”, optionally-substituted“—(C₀₋₃)alkyl-S(O)—X”, optionally-substituted “—S(O)—(C₁₋₃)alkyl-X”,optionally-substituted “(C₀₋₃)alkyl-S(O)₂—X”, optionally-substituted“—S(O)₂—(C₁₋₃)alkyl-X”, optionally-substituted “—(C₁₋₃)alkyl-N(R⁵)—X”,optionally-substituted “—(C₁₋₃)alkyl-N(R⁵)C(O)—X”,optionally-substituted “—(C₁₋₃)alkyl-C(O)N(R⁵)—X”, andoptionally-substituted “—(C₁₋₆)alkyl-X” mean that the alkyl groups inthese moieties are optionally substituted by one or more (e.g., one tosix) same or different substituents as provided in the definitionsection.

In one embodiment, U is

In certain embodiments, the compounds of Formula I have at least threeof Z¹, Z², Z³, Z⁴, and Z⁵ being CH. One embodiment provides that each ofZ¹, Z², Z³, Z⁴, and Z⁵ is CH.

In one embodiment of Formula I, at least three of W¹, W², W³, and W⁴,independently, are C(R³). In another embodiment, each of W¹, W², W³, andW⁴, independently, is C(R³). In one embodiment, each of W¹, W², W³, andW⁴ is CH.

In certain embodiments of the compounds of Formula I, G is alkyl,alkoxy, amino, amide, aryl, cycloalkyl, R⁶OC(O)—, R⁶C(O)O—,(R⁶)₂NC(O)O—, heterocyclyl, heteroaryl, or sulfonamide, which is furtheroptionally substituted by one or more (e.g., one to three) substituentsindependently (when applicable) selected from the group consisting ofhalogen, hydroxyl, alkoxy, nitro, cyano, haloalkoxy, alkyl,(amino)alkyl, haloalkyl, hydroxyalkyl, (dihydroxy)alkyl (also referredto as “diolalkyl”), (alkyl)carbonyl, (alkyl)sulfonyl, (aryl)sulfonyl,carboxamido, (carboxamido)alkyl, (carboxy)alkyl, (alkoxy)carbonyl,ureido, guanidino, carboxy, carboxyalkyl, cycloalkyl, alkenyl, alkynyl,aryloxy, aralkyloxy, alkylthio, sulfonamido, arylcarbonyl, and the like.In certain embodiments, all of the above optional substituents for G arefurther optionally substituted by one or more (e.g., one to three)moieties independently selected from halogen, (hydroxyl)alkyl, alkoxy,(carboxy)alkyl, (sulfonamido)alkyl, (carboxamido)alkyl, and the like.

For example, non-limiting exemplary G groups include those delineatedinfra. and those provided as follows:

1) an amino group substituted by (carboxamido)alkyl, which is furtheroptionally substituted by one or more (e.g., one to three) substitutentsselected from the group consisting of alkyl, hydroxyalkyl,(carboxy)alkyl, and (carboxamido)(C₁₋₃)alkyl; for example, G is

wherein R⁸ is H, (C₁₋₃)alkyl, —(C₁₋₃)alkyl-OH, —(C₁₋₃) alkyl-C(O)OH, or—(C₁₋₃)alkyl-C(O)N(R⁷)₂ (definitions for R⁷ are provided infra.);

2) a 5- or 6-membered heterocyclyl group optionally substituted bycarboxamido, (carboxamido)alkyl, alkyl, (alkyl)sulfonyl,(alkyl)carbonyl, carboxy, (alkoxy)carbonyl, or halogen; for example, Gis

wherein R⁹ is H, —(C₁₋₃)alkyl-C(O)NH₂, —C(₁₋₃)alkyl-C(O)N((C₁₋₃)alkyl)₂,—C(O)OH, —C(O)NH₂, —C(O)(C₁₋₃)alkyl, C(O)O(C₁₋₄)alkyl,—S(O)₂(C₁₋₃)alkyl, (C₁₋₃)alkyl, or halogen;

3) a 5- or 6-membered heteroaryl group optionally substituted by one ortwo substituents independently selected from carboxamido,(carboxamido)alkyl, haloalkoxy, haloalkyl, halo, and alkyl; for example,G is

wherein R¹⁰ is H, (C₁₋₃)alkyl, (carboxamido)(C₁₋₃)alkyl (e.g.,—(C₁₋₃)alkyl-C(O)NH₂), or —C(O)NH₂; and R¹¹ is H, halogen, (C₁₋₃)alkyl,halo(C₁₋₃)alkoxy, or halo(C₁₋₃)alkyl.

In a separate embodiment of Formula I, X is an aryl group optionallysubstituted by one or more (e.g., one to three) substituents as abovedefined. The substituents are also referred to as “M” groups infra. Inanother embodiment, X is a heteroaryl group optionally substituted byone or more (e.g., one to three) substituents (also referred to as “M”groups herein) as above defined.

In another embodiment, the invention provides a compound of Formula II,or a pharmaceutically acceptable salt, solvate, hydrate, or diastereomerthereof:

Wherein

m is 0, 1, 2, 3, 4, 5, or 6;

—Y—X is selected from the group consisting of

-   -   a) —O—(C₀₋₃)alkyl-X, which is optionally substituted;    -   b) —(C₀₋₃)alkyl-S—X, which is optionally substituted;    -   c) —S—(C₁₋₃)alkyl-X, which is optionally substituted; and    -   d) —(C₁₋₆)alkyl-X, which is optionally substituted;

X is optionally-substituted aryl or optionally-substituted heteroaryl;

E is a bond or carbonyl;

G is alkoxy, amino, amide, aryl, cycloalkyl, R⁶OC(O)—, R⁶C(O)O—,(R⁶)₂NC(O)O—, heterocyclyl, heteroaryl, or sulfonamide, wherein each ofthe alkoxy, amino, amide, aryl, cycloalkyl, heterocyclyl, heteroaryl,R⁶OC(O)—, R⁶C(O)O—, (R⁶)₂NC(O)O—, and sulfonamide is optionallysubstituted;

R¹ and R², each independently, are H, alkyl, amide, amino, cyano,alkoxy, hydroxyl, halogen, cycloalkyl, aryl, heteroaryl, orheterocyclyl, wherein each of the alkyl, alkoxy, amide, amino,cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionallysubstituted;

R³ and R⁴, each independently, are H, alkyl, alkoxy, amide, amino,R⁶OC(O)—, R⁶C(O)O—, cyano, cycloalkyl, heterocyclyl, hydroxyl, halogen,sulfonamide, or nitro, wherein each of said alkyl, alkoxy, amide, amino,R⁶OC(O)—, R⁶C(O)O—, cycloalkyl, heterocyclyl, and sulfonamide groups isoptionally substituted; and

R⁶, on each occurrence, independently is H, alkyl, aryl, cycloalkyl,heteroaryl, or heterocyclyl, wherein each of said alkyl, aryl,cycloalkyl, heteroaryl, and heterocyclyl is optionally substituted;

Provided that

-   -   when —Y—X is —O—CH₂—X, then X is further substituted (i.e., by a        group other than H); and    -   when —Y—X is —(C₁₋₆)alkyl-X and X is aryl, then said (C₁₋₆)alkyl        in —Y—X is further optionally substituted by (C₁₋₃)alkyl,        hydroxyl, halogen, (C₁₋₃)alkoxy, amide, amino,        ((C₁₋₃)alkyl)amino, halo(C₁₋₃)alkyl, or (C₁₋₃)alkoxy.

In certain embodiments, the Compounds of the Invention are compounds ofany one of Formulae I and II, wherein E is a bond, and pharmaceuticallyacceptable salts, solvates, hydrates, or diastereomers thereof.

In one embodiment of Formula I or II, all R^(a)s are hydrogen.

In a separate embodiment of Formula I or II, R⁴ is H.

In another embodiment, the invention provides a compound of Formula III,or a pharmaceutically acceptable salt, solvate, hydrate, or diastereomerthereof:

Wherein

m is 0, 1, 2, 3, or 4;

—Y—X is selected from the group consisting of

-   -   a) —O—(C₀₋₃)alkyl-X, which is optionally substituted;    -   b) —(C₀₋₃)alkyl-S—X, which is optionally substituted; and    -   c) —S—(C₁₋₃)alkyl-X, which is optionally substituted;

X is optionally-substituted aryl or optionally-substituted heteroaryl;

G is alkoxy, amino, amide, aryl, cycloalkyl, R⁶OC(O)—, R⁶C(O)O—,(R⁶)₂NC(O)O—, heterocyclyl, heteroaryl, or sulfonamide, wherein each ofthe alkoxy, amino, amide, aryl, cycloalkyl, heterocyclyl, heteroaryl,R⁶OC(O)—, R⁶C(O)O—, (R⁶)₂NC(O)O—, and sulfonamide is optionallysubstituted;

R¹ and R², each independently, are H, alkyl, amide, amino, cyano,alkoxy, hydroxyl, halogen, cycloalkyl, aryl, heteroaryl, orheterocyclyl, wherein each of the alkyl, alkoxy, amide, amino,cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionallysubstituted;

R³ each independently is H, alkyl, alkoxy, amide, amino, R⁶OC(O)—,R⁶C(O)O—, cyano, cycloalkyl, heterocyclyl, hydroxyl, halogen,sulfonamide, or nitro, wherein each of said alkyl, alkoxy, amide, amino,R⁶OC(O)—, R⁶C(O)O—, cycloalkyl, heterocyclyl, and sulfonamide groups isoptionally substituted; and

R⁶, on each occurrence, independently is H, alkyl, aryl, cycloalkyl,heteroaryl, or heterocyclyl, wherein each of said alkyl, aryl,cycloalkyl, heteroaryl, and heterocyclyl is optionally substituted;

Provided that when —Y—X is —O—CH₂—X, then X is further substituted by agroup other than H.

In one embodiment of the compounds of any one of Formulae I to III, atleast three of R³s are hydrogen.

In another embodiment, the Compounds of the Invention are compounds ofFormula IV, and pharmaceutically acceptable salts, solvates, hydrates,and diastereomers thereof:

Wherein

m is 0, 1, 2, or 3;

—Y—X is —O—(C₀₋₃)alkyl-X;

X is optionally-substituted aryl or optionally-substituted heteroaryl;

R¹ and R², each independently, are H, optionally-substituted 3 to7-membered heterocyclyl, or optionally-substituted (C₁₋₆)alkyl;

G is selected from the group consisting of alkoxy, amino, cycloalkyl,heterocyclyl, and heteroaryl, and

i) when G is alkoxy, cycloalkyl, heterocyclyl, or heteroaryl, then eachof the alkoxy, cycloalkyl, heterocyclyl, and heteroaryl is furtheroptionally substituted by one or more (e.g., one to three) substituentsindependently selected from the group consisting of:

-   -   a) —(C₀₋₆)alkyl-C(O)N(R⁷)₂ optionally substituted by one or more        (e.g., one to three) substituents independently selected from        the group consisting of —(C₁₋₃)alkyl, —(C₀₋₃)alkyl-OH,        (C₁₋₃)alkoxy, —(C₀₋₃)alkyl-C(O)OH, —(C₀₋₃)alkyl-S(O)₂NH₂, and        —(C₀₋₃)alkyl-C(O)N(R⁷)₂;    -   b) (C₁₋₆)alkyl optionally substituted by one or more (e.g., one        to three) substituents independently selected from the group        consisting of hydroxyl, —NH₂, —(C₀₋₃)alkyl-OH, halogen,        —(C₀₋₃)alkyl-C(O)OH, and —(C₀₋₃)alkyl-C(O)N(R⁷)₂;    -   c) (C₁₋₆)alkoxy optionally substituted by one or more (e.g., one        to three) same or different halogens;    -   d) —OH;    -   e) ureido;    -   f) halogen;    -   g) —C(O)(C₁₋₆)alkyl;    -   h) —C(O)O(C₁₋₆)alkyl;    -   i) —S(O)₂(C₁₋₆)alkyl; and    -   j) —S(O)₂N(R⁷)₂;

ii) when G is amino, said amino is further optionally substituted by oneor two substituents independently selected from the group consisting of:

-   -   1) —(C₀₋₆)alkyl-C(O)N(R⁷)₂ optionally substituted by one or more        (e.g., one to three) substituents independently selected from        the group consisting of (C₁₋₃)alkyl, —(C₀₋₃)alkyl-OH,        (C₁₋₃)alkoxy, —(C₀₋₃)alkyl-C(O)OH, —(C₀₋₃)alkyl-S(O)₂NH₂, and        —(C₀₋₃)alkyl-C(O)NH_(2;)    -   2) (C₁₋₆)alkyl optionally substituted by one or more (e.g., one        to three) substituents independently selected from the group        consisting of (C₁₋₃)alkyl, hydroxyl, —NH₂, —(C₀₋₃)alkyl-OH,        halogen, —(C₀₋₃)alkyl-C(O)OH, and —(C₀₋₃)alkyl-C(O)N(R⁷)₂;    -   3) —C(O)(C₁₋₆)alkyl;    -   4) —C(O)O(C₁₋₆)alkyl; and    -   5) —S(O)₂(C₁₋₆)alkyl;

R⁷, each independently, is H or (C₁₋₆)alkyl;

R³ is H, (C₁₋₆)alkyl, (C₁₋₆)alkoxy, amide, amino, R⁶OC(O)—, R⁶C(O)O—,cyano, (C₃₋₇)cycloalkyl, 4- to 8-membered heterocyclyl, hydroxyl,halogen, sulfonamide, or nitro, wherein each of said (C₁₋₆)alkyl,(C₁₋₆)alkoxy, amide, amino, R⁶OC(O)—, R⁶C(O)O—, (C₃₋₇)cycloalkyl, 4- to8-membered heterocyclyl, and sulfonamide groups is optionallysubstituted; and

R⁶, on each occurrence, independently is H, (C₁₋₆)alkyl, 6- to10-membered aryl, (C₃₋₇)cycloalkyl, 5- to 6-membered heteroaryl, or 4-to 8-membered heterocyclyl, wherein each of said (C₁₋₆)alkyl, said 6- to10-membered aryl, said (C₃₋₇)cycloalkyl, said 5- to 6-memberedheteroaryl, and said 4- to 8-membered heterocyclyl is optionallysubstituted;

Provided that when —Y—X is —O—CH₂—X, then X is further substituted(i.e., by a group other than H).

One embodiment of the compounds in accordance with any one of Formulae Ito IV provides that —Y—X is —O—X. In another embodiment, —Y—X is—O—(C₁₋₃)alkyl-X.

In one embodiment of Formulae I to IV, one of R¹ and R² is H, and theother is H, optionally-substituted 3- to 7-membered heterocyclyl (e.g.,

wherein R¹² is H, (C₁₋₃)alkyl, or carboxamido), or (C₁₋₃)alkyl (e.g.,methyl and ethyl).

In a separate embodiment, the invention provides the compounds of anyone of Formulae I to IV, and pharmaceutically acceptable salts,solvates, hydrates, and diastereomers thereof, wherein X is phenyl or6-membered heteroaryl, with each of said phenyl and said 6-memberedheteroaryl being optionally substituted. For example, X can be phenyl,pyridyl, or pyrimidyl, wherein each of said phenyl, pyridyl, andpyrimidyl is optionally substituted.

In one instance, X is phenyl that is optionally substituted by one tothree same or different substituents. The substituents include any arylsubstituents as above discussed. In one embodiment, the substituents areselected from the group consisting of halogen, haloalkyl, haloalkoxy,(alkyl)amino, amino, and (dialkyl)amino.

In another embodiment, the Compounds of the Invention are compounds ofFormula V, and pharmaceutically acceptable salts, solvates, hydrates,and diastereomers thereof:

Wherein

Y is —O— or —O—CH₂—;

m is 0, 1, or 2;

M is halogen, haloalkyl, haloalkoxy, (alkyl)amino, amino, or(dialkyl)amino;

R¹ and R², each independently, are H or (C₁₋₃)alkyl;

R³ is H, (C₁₋₃)alkyl, (C₁₋₃)alkoxy, amino, hydroxyl, or halogen;

G is selected from the group consisting of

-   -   i) amino optionally substituted by        -   1) —(C₀₋₃)alkyl-C(O)N(R⁷)₂ further optionally substituted by            one or more (e.g., one to three) substituents independently            selected from the group consisting of (C₁₋₃)alkyl,            —(C₀₋₃)alkyl-OH, —(C₁₋₃)alkoxy, —(C₀₋₃)alkyl-C(O)OH,            —(C₀₋₃)alkyl-S(O)₂NH₂, and —(C₀₋₃)alkyl-C(O)NH_(2;)        -   2) (C₁₋₃)alkyl optionally substituted by one or more (e.g.,            one to three) substituents independently selected from the            group consisting of (C₁₋₃)alkyl, hydroxyl, —NH₂,            —(C₀₋₃)alkyl-OH, halogen, —(C₀₋₃)alkyl-C(O)OH, and            —(C₀₋₃)alkyl-C(O)N(R⁷)₂;        -   3) —C(O)O(C₁₋₃)alkyl; or        -   4) —C(O)(C₁₋₃)alkyl;    -   ii) 3 to 7-membered heterocyclyl optionally substituted by one        or more substituents independently selected from the group        consisting of        -   a) —(C₀₋₃)alkyl-C(O)N(R⁷)₂ further optionally substituted by            one or more substituents independently selected from the            group consisting of (C₁₋₃)alkyl, —(C₀₋₃)alkyl-OH,            —(C₁₋₃)alkoxy, —(C₀₋₃)alkyl-C(O)OH, —(C₀₋₃)alkyl-S(O)₂NH₂,            and —(C₀₋₃)alkyl-C(O)NH₂;        -   b) (C₁₋₃)alkyl optionally substituted by one or more (e.g.,            one to three) substituents independently selected from the            group consisting of (C₁₋₃)alkyl, hydroxyl, —NH₂,            —(C₀₋₃)alkyl-OH, halogen, —(C₀₋₃)alkyl-C(O)OH, and            —(C₀₋₃)alkyl-C(O)N(R⁷)₂;        -   c) (C₁₋₃)alkoxy optionally substituted by one or more (e.g.,            one to three) same or different halogens;        -   d) halogen;        -   e) —S(O)₂(C₁₋₃)alkyl;        -   f) —C(O)O(C₁₋₃)alkyl; and        -   g) —C(O)(C₁₋₃)alkyl;    -   and iii) 5- to 6-membered heteroaryl optionally substituted by        one or more (e.g., one to three) substituents independently        selected from the group consisting of the a)-g) moieties as        above defined; and

R⁷ independently is H or (C₁₋₃)alkyl.

In one embodiment, the Compounds of the Invention are compounds of anyone of Formula I to V, and pharmaceutically acceptable salts, solvates,hydrates, and diastereomers thereof, wherein Y is —O—.

In one embodiment, the compounds of Formula V have M as halogen (e.g.,F). In another embodiment of Formula V, M is haloalkyl (such as, —CF₃).

Certain embodiments in accordance with any one of the above formulaeprovide that one of R¹ and R² is H, and the other is (C₁₋₃)alkyl.

In one embodiment, the Compounds of the Invention are compounds of anyone of the above formulae, and pharmaceutically acceptable salts,solvates, hydrates, and diastereomers thereof, wherein G isoptionally-substituted 3- to 7-membered heterocyclyl (including thosediscussed supra.).

Further, non-limiting exemplary 3- to 7-membered heterocyclyl groupsthat can be used herein as a G group include oxiranyl, aziridinyl,azetidinyl, oxo-azetidinyl, tetrahydrofuranyl, tetrahydro-pyranyl,pyrrolidinyl, oxo-pyrrolidinyl, piperidyl, oxo-piperidyl, and the like.

Moreover, G can be a 3- to 7-membered heterocyclyl moiety that isoptionally substituted by one or more (e.g., one, two, or three)substituents independently selected from the group consisting ofhalogen, optionally-substituted (C₁₋₃)alkyl, —C(O)O(C₁₋₃) alkyl,—C(O)C(₁₋₃)alkyl, —S(O)₂(C₁₋₃)alkyl, and optionally-substituted—(C₀₋₃)alkyl-C(O)N(R⁷)₂.

In one embodiment, G is a 3- to 7-membered heterocyclyl moiety selectedfrom the group consisting of:

wherein any one of the above 3- to 7-membered heterocyclyl moieties isfurther optionally substituted by one or two same or differentsubstituents selected from the group consisting of halogen,—(C₀₋₃)alkyl-C(O)N(R⁷)₂, —C(O)O(C₁₋₃)alkyl, —C(O)(C₁₋₃)alkyl,—SO₂(C₁₋₃)alkyl, and (C₁₋₃)alkyl. In certain embodiments, R⁷, eachindependently, is H or (C₁₋₃)alkyl.

In an embodiment, G is a 5- or 6-membered heterocyclyl group optionallysubstituted by carboxamido, (carboxamido)alkyl, alkyl, (alkyl)sulfonyl,(alkyl)carbonyl, or halogen. For example, G is

wherein R⁹ is H, —C(₁₋₃)alkyl-C(O)NH₂, —C(₁₋₃)alkyl-C(O)N((C₁₋₃)alkyl)₂,—C(O)OH, —C(O)NH₂, —C(O)(C₁₋₃)alkyl, —C(O)O(C₁₋₄)alkyl,—S(O)₂(C₁₋₃)alkyl, C(₁₋₃)alkyl, or halogen. In one embodiment, G is

In another embodiment, G is

wherein R⁹ is H, —C(₁₋₃)alkyl-C(O)NH₂, —C(₁₋₃)alkyl-C(O)N((C₁₋₃)alkyl)₂,or —C(O)O(C₁₋₄)alkyl. In still another embodiment, G is

wherein R⁹ is H, —C(₁₋₃)alkyl-C(O)NH₂, —C(O)NH₂, or —C(O)O(C₁₋₄)alkyl.In another embodiment, G is

wherein R⁹ is H, —C(O)NH₂, or —C(O)OH.

In another embodiment, the Compounds of the Invention are compounds ofany one of the above formulae, and pharmaceutically acceptable salts,solvates, hydrates, and diastereomers thereof, wherein G is a heteroarylgroup including those discussed supra.

Further, as a separate embodiment, G is an optionally-substituted 5- to6-membered heteroaryl moiety selected from the group consisting offuranyl, thiophenyl, imidazyl, triazolyl, triazinyl, tetrazolyl,pyrazolyl, pyridinyl, and pyrimidyl, each of which is further optionallysubstituted by one or more (e.g., one to three) substituentsindependently selected from the group consisting of halogen,optionally-substituted (C₁₋₃)alkyl, halo(C₁₋₃)alkoxy, andoptionally-substituted —(C₀₋₃)alkyl-C(O)N(R⁷)₂. In one embodiment, R⁷ asused herein, each independently, is H or (C₁₋₃)alkyl.

Non-limiting exemplary 5- to 6-membered heteroaryl groups that can beused as G include those provided as follows:

wherein each of the above exemplified 5- to 6-membered heteroaryl groupsis further optionally substituted by one or more (e.g., one to three)substituents independently selected from the group consisting ofhalogen, (C₁₋₃)alkyl, —(C₀₋₃)alkyl-C(O)N(R⁷)₂, halo(C₁₋₃)alkyl, andhalo(C₁₋₃)alkoxy. In one embodiment, R⁷ as used herein, eachindependently, is H or (C₁₋₃)alkyl.

In another embodiment, G is a 5- or 6-membered heteroaryl groupoptionally substituted by one or two substituents independently selectedfrom the group consisting of carboxamido, (carboxamido)alkyl,haloalkoxy, haloalkyl, halo, and alkyl.

For example, G is

wherein R¹⁰ is H, (C₁₋₃)alkyl, —(C₁₋₃)alkyl-C(O)NH₂, or —C(O)NH₂; andR^(H) is H, halogen, (C₁₋₃)alkyl, halo(C₁₋₃)alkoxy, or halo(C₁₋₃)alkyl.

In still another embodiment, the Compounds of the Invention arecompounds of any one of the above formulae, and pharmaceuticallyacceptable salts, solvates, hydrates, and diastereomers thereof, whereinG is optionally-substituted amino (including those above delineated). Asa further example, G is —NH(C₁₋₃)alkyl that may be further optionallysubstituted by one or more (e.g., one to three) substituents, which canbe the same or different. Non-limiting exemplary substituents include(C₁₋₃)alkyl, —C(O)N(R⁷)₂, —OH, and —C(O)OH. In one embodiment, R⁷ asused herein, each independently, is H or (C₁₋₃)alkyl.

In other embodiments, G is an amino group substituted by(carboxamido)alkyl, which is further optionally substituted by one ormore (e.g., one to three) substitutents selected from the groupconsisting of (C₁₋₃)alkyl, —(C₁₋₃)alkyl-OH, —(C₀₋₃)alkyl-C(O)OH, and—(C₀₋₃)alkyl-C(O)N(R⁷)₂.

For example, G is

wherein R⁸ is H, (C₁₋₃)alkyl, —(C₁₋₃)alkyl-OH, —(C₁₋₃)alkyl-C(O)OH, or—(C₁₋₃)alkyl-C(O)N(R⁷)₂. One embodiment provides that R⁷ is H.

Further, non-limiting exemplary optionally-substituted amino groups thatcan be used as G include, for example, the following moieties:

In one embodiment, the Compounds of the Invention are compounds havingany one of the above formulae, wherein R³ is H, and the pharmaceuticallyacceptable salts, solvates, hydrates, and diastereomers thereof.

In certain embodiments, the Compounds of the Invention include exemplarycompounds provided in TABLE 2 as follows:

TABLE 2 Compd No. Structure Chemical Name  9

1-(4-(4-fluorophenoxy)phenyl)-2- (tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole 10

2-(4-chloro-1-methyl-1H-pyrazol-3-yl)- 1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazole 11

1-(4-(4-fluorophenoxy)phenyl)-2-(1H- imidazol-4-yl)-1H-benzo[d]imidazole14

(S)-5-(1-(4-(4-fluorophenoxy)-phenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2- one 15

2-((1H-tetrazol-5-yl)methyl)-1-(4-(4- fluorophenoxy)phenyl)-1H-benzo[d]imidazole 16

1-(4-(4-fluorophenoxy)phenyl)-2-((5-methyl-4H-1,2,4-triazol-3-yl)methyl)- 1H-benzo[d]imidazole 17

1-(4-(4-fluorophenoxy)phenyl)-2-(2- (piperidin-1-yl)ethyl)-1H-benzo[d]imidazole 18

tert-butyl (S)-2-(1-(4-(4- fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1- carboxylate 19

tert-butyl 4-(1-(4-(4-fluorophenoxy) phenyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate 20

1-(4-(4-fluorophenoxy)phenyl)-2- (piperidin-4-yl)-1H-benzo[d]imidazole21

(S)-1-(4-(4-fluorophenoxy)phenyl)-2-(pyrrolidin-2-yl)-1H-benzo[d]imidazole 23

2-(4-(1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)piperidin-1- yl)acetamide 24

N,N-diethyl-2-(4-(1-(4-(4- fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)piperidin-1- yl)acetamide 25

(S)-2-(2-(1-(4-(4-fluorophenoxy) phenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)acetamide 26

2-(((1-(4-(4-(trifluoromethyl) phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)amino)- acetamide 27

2-((1-(1-(4-(4-(trifluoromethyl) phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino) acetamide 28

2-((1-(1-(4-(4-(trifluoromethyl) phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino) propanamide 29

2-(((1-(4-(4-(trifluoromethyl) phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)amino) propanamide 30

3-hydroxy-2-(((1-(4-(4- (trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)- amino)propanamide 31

3-hydroxy-2-((1-(1-(4-(4- (trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2- yl)ethyl)amino)propanamide 32

1-(1-(1-(4-(4-(trifluoromethyl) phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethyl)pyrrolidine-2- carboxamide 33

1-((1-(4-(4-(trifluoromethyl) phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)pyrrolidine-2- carboxamide 34

5-amino-5-oxo-4-((1-(1-(4-(4- (trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethyl)- amino)pentanoic acid 35

2-((1-(1-(4-(4-(trifluoromethyl) phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethyl) amino)pentanediamide 36

2-(((1-(4-(4-(trifluoromethyl) phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)amino) pentanediamide 37

5-amino-5-oxo-4-(((1-(4-(4- (trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2- yl)methyl)amino)pentanoic acid 38

1-(4-(4-fluorophenoxy)phenyl)-2-((1- methyl-1H-tetrazol-5-yl)methyl)-1H-benzo[d]imidazole 39

1-(5-((1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)-1H- tetrazol-1-yl)ethan-1-one 40

1-(4-(4-fluorophenoxy)phenyl)-2-((1- (methylsulfonyl)-1H-tetrazol-5-yl)methyl)-1H-benzo[d]imidazole 41

5-((1-(4-(4-fluorophenoxy)phenyl)-1H- benzo[d]imidazol-2-yl)methyl)-N-methyl-1H-tetrazole-1-carboxamide 42

5-oxo-1-((1-(4-(4-(trifluoromethyl)-phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)pyrrolidine-2-carboxylic acid 43

5-oxo-1-((1-(4-(4-(trifluoromethyl)-phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)pyrrolidine-2-carboxamide

In a certain embodiment, the Compounds of the Invention include thefollowing compounds:

and the pharmaceutically acceptable salts, solvates, hydrates, anddiastereomers thereof.

In another embodiment, the Compounds of the Invention include thefollowing compounds:

and the pharmaceutically acceptable salts, solvates, hydrates, anddiastereomers thereof.

In yet another embodiment, the invention provides the followingcompounds:

and the pharmaceutically acceptable salts, solvates, hydrates, anddiastereomers thereof.

Some of the compounds disclosed herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms. The invention is meant to encompass theuse of all such possible forms, as well as their racemic and resolvedforms and mixtures thereof. The individual enantiomers can be separatedaccording to methods well known in the art in view of the presentdisclosure. When the compounds described herein contain olefinic doublebonds or other centers of geometric asymmetry, and unless specifiedotherwise, it is intended that they include both E and Z geometricisomers. All tautomers are intended to be encompassed by the presentinvention as well.

The invention also encompasses any of the disclosed compounds beingisotopically-labelled (i.e., radiolabeled) by having one or more atomsreplaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, ²H, ³H, ¹¹C, ¹³C, ¹⁴C,¹⁵N, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively, and preferably ³H, ¹¹C,and ¹⁴C. Isotopically-labeled compounds of the present invention can beprepared by methods known in the art.

The invention is also directed to ³H, ¹¹C, or ¹⁴C radiolabeled compoundsof any of the above formulae, as well as their pharmaceuticallyacceptable salts, solvates, hydrates, diastereomers, and prodrugsthereof, and the use of any such compounds as radioligands for theirability to bind to the sodium channel. For example, one use of thelabeled Compounds of the Invention is the characterization of specificreceptor binding. Another use of a labeled Compound of the Invention isan alternative to animal testing for the evaluation ofstructure-activity relationships. For example, the receptor assay can beperformed at a fixed concentration of a labeled Compound of theInvention and at increasing concentrations of a test compound in acompetition assay. For example, a tritiated compound of any of FormulaeI to V can be prepared by introducing tritium into the particularcompound, for example, by catalytic dehalogenation with tritium. Thismethod may include reacting a suitably halogen-substituted precursor ofthe compound with tritium gas in the presence of a suitable catalyst,for example, Pd/C, in the presence or absence of a base. Other suitablemethods for preparing tritiated compounds can be found in Filer,Isotopes in the Physical and Biomedical Sciences, Vol. 1, LabeledCompounds (Part A), Chapter 6 (1987). ¹⁴C-labeled compounds can beprepared by employing starting materials having a ¹⁴C carbon.

The invention also encompasses the use of salts of the disclosedcompounds, including all non-toxic pharmaceutically acceptable saltsthereof of the disclosed compounds. Examples of pharmaceuticallyacceptable addition salts include inorganic and organic acid additionsalts and basic salts.

The pharmaceutically acceptable salts include, but are not limited to,metal salts such as sodium salt, potassium salt, cesium salt and thelike; alkaline earth metals such as calcium salt, magnesium salt and thelike; organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like;inorganic acid salts such as hydrochloride, hydrobromide, phosphate,sulphate and the like; organic acid salts such as citrate, lactate,tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate,trifluoroacetate, oxalate, formate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; andamino acid salts such as arginate, asparginate, glutamate and the like.

Acid addition salts can be formed by mixing a solution of the particularCompound of the Invention with a solution of a pharmaceuticallyacceptable non-toxic acid such as hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or thelike. Basic salts can be formed by mixing a solution of the Compound ofthe Invention with a solution of a pharmaceutically acceptable non-toxicbase such as sodium hydroxide, potassium hydroxide, choline hydroxide,sodium carbonate and the like.

The invention also encompasses solvates of any of the disclosedcompounds. Solvates typically do not significantly alter thephysiological activity or toxicity of the compounds, and as such mayfunction as pharmacological equivalents. The term “solvate” as usedherein is a combination, physical association and/or solvation of aCompound of the Invention with a solvent molecule such as, e.g. adisolvate, monosolvate or hemisolvate, where the ratio of solventmolecule to a Compound of the Invention is 2:1, 1:1 or 1:2,respectively. This physical association involves varying degrees ofionic and covalent bonding, including hydrogen bonding. In certaininstances, the solvate can be isolated, such as when one or more solventmolecules are incorporated into the crystal lattice of a crystallinesolid. Thus, “solvate” encompasses both solution-phase and isolatablesolvates. Compounds of any of Formulae I to V can be present as solvatedforms with a pharmaceutically acceptable solvent, such as water,methanol, ethanol, and the like, and it is intended that the inventionincludes both solvated and unsolvated forms of compounds of any ofFormulae I to V.

Further, the invention encompasses hydrates of any of the disclosedcompounds. It is appreciated that a hydrate may be considered as aspecific type of solvate. In other words, it may be appreciated in theart that a “hydrate” is a particular subgroup of solvates where thesolvent molecule is water.

Solvates typically can function as pharmacological equivalents.Preparation of solvates is known in the art. See, for example, M. Cairaet a.l, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes thepreparation of solvates of fluconazole with ethyl acetate and withwater. Similar preparation of solvates, hemisolvates, hydrates, and thelike are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech.,5(1): Article 12 (2004), and A. L. Bingham et al., Chem. Commun.:603-604 (2001). A typical, non-limiting, process of preparing a solvatewould involve dissolving a compound of any of the formulae discussedabove in a desired solvent (organic, water, or a mixture thereof) attemperatures above 20° C. to about 25° C., then cooling the solution ata rate sufficient to form crystals, and isolating the crystals by knownmethods, e.g., filtration. Analytical techniques such as infraredspectroscopy can be used to confirm the presence of the solvent in acrystal of the solvate.

The invention is also meant to encompass prodrugs of any of thedisclosed compounds. As used herein, prodrugs are considered to becompounds with moieties that can be metabolized in vivo. In general,such prodrugs will be functional derivatives of compounds of any of theformulae delineated herein, which will be readily convertible in vivo,e.g., by being metabolized, into the required compound of any of theformulae. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described in, for example, Design ofProdrugs, H. Bundgaard ed., Elsevier (1985); “Drug and Enzyme Targeting,Part A,” K. Widder et al. eds., Vol. 112 in Methods in Enzymology,Academic Press (1985); Bundgaard, “Design and Application of Prodrugs,”Chapter 5 (pp. 113-191) in A Textbook of Drug Design and Development, P.Krogsgaard-Larsen and H. Bundgaard eds., Harwood Academic Publishers(1991); Bundgaard et al., Adv. Drug Delivery Revs. 8:1-38 (1992);Bundgaard et al., J. Pharmaceut. Sci. 77:285 (1988); and Kakeya et al.,Chem. Pharm. Bull. 32:692 (1984).

Examples of prodrugs and their use are well known in the art (e.g.,Berge et al. (1997) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).Non-limiting examples of prodrugs include esters or amides of Compoundsof the Invention having carboxy, hydroxy or amino groups as asubstituent, and these can be prepared by reacting such parent compoundswith anhydrides such as succinic anhydride.

Methods and Use of the Compounds of the Invention

In certain embodiments, the Compounds of the Invention act as blockersof one or more sodium (Na⁺) channels. Consequently, a number of diseasesand conditions mediated by sodium ion influx can be treated by employingthe Compounds of the Invention. The invention thus provides generally amethod for treating a disorder responsive to blockade of one or moresodium channels in an animal (e.g., a human) suffering from, or at riskof suffering from, said disorder. In one embodiment, the method of theinvention comprises a step of administering to the animal an effectiveamount of a Compound of the Invention.

The invention further provides a method of modulating one or more sodiumchannels in an animal identified as in need thereof, said methodcomprising administering to the animal a modulating-effective amount ofat least one Compound of the Invention.

In one embodiment, the invention provides a method of treating stroke,neuronal damage resulting from head trauma, epilepsy, neuronal lossfollowing global and focal ischemia, pain (e.g., acute pain, chronicpain, which includes but is not limited to neuropathic pain,postoperative pain, and inflammatory pain, or surgical pain), aneurodegenerative disorder (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS), or Parkinson's disease), migraine, manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia. In one embodiment, theinvention provides a method of treating pain.

In another embodiment, the type of pain is chronic pain. In anotherembodiment, the type of pain is neuropathic pain. In another embodiment,the type of pain is postoperative pain. In another embodiment, the typeof pain is inflammatory pain. In another embodiment, the type of pain issurgical pain. In another embodiment, the type of pain is acute pain.

In another embodiment, the treatment of pain (e.g., chronic pain, suchas neuropathic pain, postoperative pain, or inflammatory pain, acutepain or surgical pain) is preemptive. In another embodiment, thetreatment of pain is palliative. In each instance, such method oftreatment requires administering to an animal in need of such treatmentan amount of a Compound of the Invention that is therapeuticallyeffective in achieving said treatment. In one embodiment, the amount ofsuch compound is the amount that is effective to block sodium channelsin vivo.

Chronic pain includes, but is not limited to, inflammatory pain,postoperative pain, cancer pain, osteoarthritis pain associated withmetastatic cancer, trigeminal neuralgia, acute herpetic and postherpeticneuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion,occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout,phantom limb pain, burn pain, and other forms of neuralgia, neuropathic,and idiopathic pain syndromes.

Chronic somatic pain generally results from inflammatory responses totissue injury such as nerve entrapment, surgical procedures, cancer orarthritis (Brower, Nature Biotechnology 2000; 18: 387-391).

The inflammatory process is a complex series of biochemical and cellularevents activated in response to tissue injury or the presence of foreignsubstances (Levine, Inflammatory Pain, In: Textbook of Pain, Wall andMelzack eds., 3^(rd) e.d., 1994). Inflammation often occurs at the siteof injured tissue, or foreign material, and contributes to the processof tissue repair and healing. The cardinal signs of inflammation includeerythema (redness), heat, edema (swelling), pain and loss of function(ibid.). The majority of patients with inflammatory pain do notexperience pain continually, but rather experience enhanced pain whenthe inflamed site is moved or touched. Inflammatory pain includes, butis not limited to, that associated with osteoarthritis and rheumatoidarthritis.

Chronic neuropathic pain is a heterogenous disease state with an unclearetiology. In chronic neuropathic pain, the pain can be mediated bymultiple mechanisms. This type of pain generally arises from injury tothe peripheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. Chronic pain is differentfrom acute pain in that patients suffer the abnormal pain sensationsthat can be described as spontaneous pain, continuous superficialburning and/or deep aching pain. The pain can be evoked by heat-, cold-,and mechano-hyperalgesia or by heat-, cold-, or mechano-allodynia.

Neuropathic pain can be caused by injury or infection of peripheralsensory nerves. It includes, but is not limited to, pain from peripheralnerve trauma, herpes virus infection, diabetes mellitus, causalgia,plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathicpain is also caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiencies. Stroke (spinal or brain) and spinal cord injury can alsoinduce neuropathic pain. Cancer-related neuropathic pain results fromtumor growth compression of adjacent nerves, brain, or spinal cord. Inaddition, cancer treatments, including chemotherapy and radiationtherapy, can also cause nerve injury. Neuropathic pain includes but isnot limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

The invention is also directed to the use of a compound represented byany one of the above formulae, or a pharmaceutically acceptable salt,hydrate, solvate, or diastereomer thereof, in the manufacture of amedicament for treating a disorder responsive to the blockade of one ormore sodium channels (e.g., any of the disorders listed above) in ananimal suffering from said disorder.

Further, the invention relates to the use of a compound represented byany one of the above formulae, or a pharmaceutically acceptable salt,hydrate, solvate, or diastereomer thereof, in the manufacture of amedicament, in particular a medicament for modulating one or more sodiumchannels, in an animal in need thereof.

General Synthetic Schemes

The Compounds of the Invention can be readily prepared using methodsknown to those skilled in the art in view of this disclosure.

For example, the compounds of Formula I can be made using conventionalorganic synthesis in view of this disclosure, or by the illustrativemethods shown in the Schemes below.

Compound A, where Q is a suitable leaving group, such as, halogen,tosylate, mesylate or triflate, is converted to Compound C by reactionwith a suitable amine (such as, Compound B) in the presence of asuitable base (such as, DIPEA) in a suitable solvent, such as, DMSO. Thenitro group in Compound C is converted to an amine, such as, the aminegroup in Compound D, by suitable reducing conditions (such as,hydrogenation) in a suitable solvent (such as, MeOH) in the presence ofa suitable catalyst (such as, Pd/C).

Compound D is converted to Compound F by reaction with a suitablealdehyde (such as, Compound E) in a suitable solvent (such as, aq. EtOH)in the presence of a suitable additive (such as, NaHSO₃). An alternateapproach is by the reaction of Compound D with a suitable acid (such as,Compound G) in the presence of a suitable coupling reagent (such as,EDCI) in a suitable solvent (such as, DCM) to give Compound H. CompoundH is then converted to Compound F by heating in a suitable solvent (suchas, toluene) in the presence of a suitable acid catalyst (such as,HOAc). Subsequent side chain modifications can be accomplished viaappropriate functional group manipulations known to one skilled in theart.

Testing of Compounds

Representative Compounds of the Invention were assessed by sodiummobilization and/or electrophysiological assays for sodium channelblocker activity. One aspect of the invention is based on the use of thecompounds herein described as sodium channel blockers. Based upon thisproperty, the Compounds of the Invention are considered useful intreating a condition or disorder responsive to the blockade of one ormore sodium ion channels, e.g., stroke, neuronal damage resulting fromhead trauma, epilepsy, seizures, general epilepsy with febrile seizures,severe myoclonic epilepsy in infancy, neuronal loss following global andfocal ischemia, migraine, familial primary erythromelalgia, paroxysmalextreme pain disorder, cerebellar atrophy, ataxia, dystonia, tremor,mental retardation, autism, a neurodegenerative disorder (e.g.,Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or Parkinson'sdisease), manic depression, tinnitus, myotonia, a movement disorder,cardiac arrhythmia, or providing local anesthesia.

In one embodiment, the Compounds of the Invention are effective intreating pain, e.g., acute pain, chronic pain, which includes but is notlimited to, neuropathic pain, postoperative pain, and inflammatory pain,or surgical pain.

In certain embodiments, the invention provides compounds of Formulae Ito V and pharmaceutically acceptable salts, solvates, hydrates, anddiastereomers thereof that are useful as blockers of one or more sodiumchannels. According to the invention, those compounds having usefulsodium channel blocking properties exhibit an IC₅₀ for Na_(v)1.1,Na_(v)1.2, Na_(v)1.3, Na_(v)1.4, Na_(v)1.5, Na_(v)1.6, Na_(v)1.7,Na_(v)1.8, and/or Na_(v)1.9 of about 100 μM or less, e.g., about 50 μMor less, about 10 μM or less, about 5 μM or less, or about 1 μM or less,in sodium mobilization and/or electrophysiological assays. In certainembodiments, Compounds of the Invention exhibit an IC₅₀ for Na_(v)1.7 of100 μM or less, about 50 μM or less, about 10 μM or less, about 5 μM orless, about 1 μM or less, about 0.5 μM or less, or about 0.1 μM or less.Compounds of the Invention can be tested for their Na⁺ channel blockingactivity using methods known in the art and by the followingfluorescence imaging and electrophysiological in vitro assays and/or invivo assays.

In one embodiment, the Compounds of the Invention demonstratesubstantially no penetration across the CNS blood-brain barrier in amammal. Such compounds are referred to as “peripherally restricted” as ameans to designate their PNS versus CNS tissue selectivity.

In one embodiment, the PNS:CNS concentration ratio of a peripherallyrestricted Compound of the Invention is about 5:1, about 10:1, about20:1, about 30:1; about 50:1; about 100:1, about 250:1, about 500:1,about 1000:1, about 5,000:1, about 10,000:1, or more. Compounds of theInvention can be tested for their ability to penetrate the centralnervous system using in vitro and in vivo methods known in the art.

In Vitro Assay Protocols FLIPR® Assays

Recombinant Na_(v)1.7 Cell Line:

In vitro assays were performed in a recombinant cell line expressingcDNA encoding the alpha subunit (Na_(v)1.7, SCN9a, PN1, NE) of humanNa_(v)1.7 (Accession No. NM_(—)002977). The cell line was provided byinvestigators at Yale University (Cummins et al, J. Neurosci. 18(23):9607-9619 (1998)). For dominant selection of the Na_(v)1.7-expressingclones, the expression plasmid co-expressed the neomycin resistancegene. The cell line was constructed in the human embryonic kidney cellline, HEK293, under the influence of the CMV major late promoter, andstable clones were selected using limiting dilution cloning andantibiotic selection using the neomycin analogue, G418. Recombinant betaand gamma subunits were not introduced into this cell line. Additionalcell lines expressing recombinant Na_(v)1.7 cloned from other speciescan also be used, alone or in combination with various beta subunits,gamma subunits or chaperones.

Non-Recombinant Cell Lines Expressing Native Na_(v)1.7:

Alternatively, in vitro assays can be performed in a cell lineexpressing native, non-recombinant Na_(v)1.7, such as the ND7 mouseneuroblastoma X rat dorsal root ganglion (DRG) hybrid cell line ND723,available from the European Cell Culture Collection (Cat. No. 92090903,Salisbury, Wiltshire, United Kingdom). The assays can also be performedin other cell lines expressing native, non-recombinant Na_(v)1.7, fromvarious species, or in cultures of fresh or preserved sensory neurons,such as dorsal root ganglion (DRG) cells, isolated from various species.Primary screens or counter-screens of other voltage-gated sodiumchannels can also be performed, and the cell lines can be constructedusing methods known in the art, purchased from collaborators orcommercial establishments, and they can express either recombinant ornative channels. The primary counter-screen is for one of the centralneuronal sodium channels, Na_(v)1.2 (rBIIa), expressed in HEK293 hostcells (Ilyin et al., Br. J. Pharmacol. 144:801-812 (2005)).Pharmacological profiling for these counter-screens is carried out underconditions similar to the primary or alternative Na_(v)1.7 assaysdescribed below.

Cell Maintenance:

Unless otherwise noted, cell culture reagents were purchased fromMediatech of Herndon, Va. The recombinant Na_(v)1.7HEK293 cells wereroutinely cultured in growth medium consisting of Dulbecco's minimumessential medium containing 10% fetal bovine serum (FBS, Hyclone, ThermoFisher Scientific, Logan, Utah), 100 Um/L penicillin, 100 μg/mLstreptomycin, 2-4 mM L-glutamine, and 500 mg/mL G418. For natural,non-recombinant cell lines, the selective antibiotic was omitted, andadditional media formulations can be applied as needed.

Assay Buffer:

The assay buffer was formulated by removing 120 mL from a 1 L bottle offresh, sterile dH₂O (Mediatech, Herndon, Va.) and adding 100 mL of10×HBSS that does not contain Ca⁺⁺ or Mg⁺⁺ (Gibco, Invitrogen, GrandIsland, N.Y.) followed by 20 mL of 1.0 M Hepes, pH 7.3 (FisherScientific, BP299-100). The final buffer consisted of 20 mM Hepes, pH7.3, 1.261 mM CaCl₂, 0.493 mM MgCl₂, 0.407 mM Mg(SO)₄, 5.33 mM KCl,0.441 mM KH₂PO₄, 137 mM NaCl, 0.336 mM Na₂HPO₄ and 0.556 mM D-glucose(Hanks et al., Proc. Soc. Exp. Biol. Med. 71:196 (1949)), and the simpleformulation was typically the basic buffer throughout the assay (i.e.,all wash and addition steps).

CoroNa™ Green AM Na⁺ Dye for Primary Fluorescence Assay:

The fluorescence indicator used in the primary fluorescence assay wasthe cell permeant version of CoroNa™ Green (Invitrogen, MolecularProbes, Eugene, Oreg.), a dye that emits light in the fluorescence range(Harootunian et al., J. Biol. Chem. 264(32):19458-19467 (1989)). Theintensity of this emission, but not the wavelength range, is increasedwhen the dye is exposed to Na⁺ ions, which it can bind with partialselectivity. Cells expressing Na_(v)1.7 or other sodium channels wereloaded with the CoroNa™ Green dye immediately in advance of thefluorescence assay, and then, after agonist stimulation, themobilization of Na⁺ ions was detected as the Na⁺ ions flowed from theextracellular fluid into the cytoplasm through the activated sodiumchannel pores. The dye was stored in the dark as a lyophilized powder,and then an aliquot was dissolved immediately before the cell loadingprocedure, according to the instructions of the manufacturer to a stockconcentration of 10 mM in DMSO. It was then diluted in the assay bufferto a 4× concentrated working solution, so that the final concentrationof dye in the cell loading buffer was 5 μM.

Membrane Potential Dye for Alternative Fluorescence Assays:

A fluorescence indicator that can be used in alternative fluorescenceassays is the blue version membrane potential dye (MDS, MolecularDevices, Sunnyvale, Calif.), a dye that detects changes in moleculesfollowing a change in membrane potential. An increase in fluorescence isexpected if agonist stimulation provokes a change in membrane potential.Cells expressing Na_(v)1.7 or other sodium channels are incubated withthe membrane potential dye 30-60 minutes before the fluorescence assay.In the case of the KCl pre-stimulation version of the assay, the dye andall other components are washed out immediately before the assay, andthe dye is then replaced. In the version lacking KCl pre-stimulation,the dye remains on the cells and is not washed out or replaced. The dyeis stored in the dark as a lyophilized powder, and then an aliquotdissolved in assay buffer to form a 20×-concentrated stock solution thatcan be used for several weeks.

Agonists:

In the fluorescence assays, two agonists were used in combination,namely 1) veratridine; and 2) the venom from the yellow scorpion,Leiurus quinquestriatus hebraeus. Veratridine is an alkaloid smallmolecule that facilitates the capture of channel openings by inhibitinginactivation, and the scorpion venom is a natural preparation thatincludes peptide toxins selective for different subsets of voltage-gatedsodium channels. These scorpion toxins inhibit the fast inactivation oftheir cognate target channels. Stock solutions of the agonists wereprepared to 40 mM in DMSO (veratridine) and 1 mg/mL in dH₂O (scorpionvenom), and then diluted to make a 4× or 2× stock (depending on theparticular assay) in assay buffer, the final concentration being 100 μM(veratridine) and 10 μg/mL (scorpion venom). Both of the agonists werepurchased from Sigma Aldrich, St. Louis, Mo.

Test Compounds:

Test compounds were dissolved in DMSO to yield 10 mM stock solutions.The stock solutions were further diluted using DMSO in 1:3 serialdilution steps with 10 points (10,000 μM, 3,333 μM, 1,111 μM, 370 μM,123 μM, 41 μM, 14 μM, 4.6 μM, 1.5 μM and 0.5 μM). The stock solutionswere further diluted in assay buffer (1:125) as 4× stock serialdilutions with a DMSO concentration of 0.8% (final [DMSO], in the assay,from the compounds component=0.2%), so that the compounds' finalconcentrations in the assay were 20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μMand 0.08 μM, 0.03 μM, 0.01 μM, 0.003 μM and 0.001 μM. If a particulartest article appeared to be especially potent, then the concentrationcurve was adjusted, e.g., to 10-fold lower concentrations, in order toperform the dose-response in a more relevant concentration range.Compound dilutions were added during the dye-loading and pre-stimulationstep, and then again during the fluorescence assay, early in the kineticread. Compound dilutions were added in duplicate rows across the middle80 wells of the 96-well plate, whereas the fully stimulated and thefully inhibited controls (positive and negative) were located in the top4 side wells and the bottom 4 side wells, respectively, on the left andright sides of the assay plate.

Data Analysis:

The data were analyzed according to methods known to those skilled inthe art or using the GraphPad® Prism 4.0 Program (available fromGraphPad Software, San Diego, Calif.) to determine the IC₅₀ value forthe test article. At least one standard reference compound was evaluatedduring each experiment.

FLIPR® or FLIPR^(TETRA)® Sodium Dye Assay with KCl and Test ArticlePre-Incubation:

Cells were prepared by plating the recombinant HEK293 cells or otherhost cells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of 40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately fewer cells andless media. The plate was then incubated in growth media, with orwithout selective antibiotic, overnight at 37° C. at 5% CO₂, 95%humidity, in preparation for the assay. For counter-screens of othervoltage-gated sodium channels, the procedure was very similar, thoughoptimal densities of cells, media and subsequent assay components can befine-tuned for the particular cell line or isoform.

The next day, at the start of the assay, the media was flicked from thecells and the wells were washed once with 50 μl/well assay buffer (1×Hank's balanced salt solution without sodium bicarbonate or phenol red,20 mM Hepes, pH 7.3) and then pre-incubated with the test articles,CoroNa™ Green AM sodium dye (for cell loading) and KCl forre-polarization and synchronization of the channels in the entirepopulation of cells. For this dye-loading and pre-stimulation step, thecomponents were added as follows, immediately after the wash step: 1)first, the compound dilutions and controls were added as 4× concentratesin assay buffer at 50 μL/well; 2) CoroNa™ Green AM dye was diluted fromthe stock solution to 20 μM in assay buffer (4× concentrate) and addedto the plate at 50 μL/well; and 3) finally, a solution of 180 mM KCl(2×) was prepared by diluting a 2M stock solution into assay buffer andthe solution was added to the cells at 100 μl/well. The cells wereincubated at 25° C. in the dark for 30 mM before their fluorescence wasmeasured.

The plates containing dye-loaded cells were then flicked to remove thepre-incubation components and washed once with 100 μL/well assay buffer.A 100 μL/well aliquot of assay buffer was added back to the plate, andthe real-time assay was commenced. The fluorescence of cells wasmeasured using a fluorescence plate reader (FLIPR^(TETRA)® or FLIPR384®,MDS, Molecular Devices, Sunnyvale, Calif.) Samples were excited byeither a laser or a PMT light source (Excitation wavelength=470-495 nM)and the emissions were filtered (Emission wavelength=515-575 nM). Theadditions of compound and the channel activators in this cell-based,medium-to-high throughput assay were performed on the fluorescence platereader and the results (expressed as relative fluorescence units) werecaptured by means of camera shots every 1-3 sec., then displayed inreal-time and stored. Generally, there was a 15 sec. base line, withcamera shots taken every 1.5 sec., then the test compounds were added,then another 120 sec. baseline was conducted, with camera shots takenevery 3 sec.; and finally, the agonist solution (containing veratridineand scorpion venom) was added. The amplitude of fluorescence increase,resulting from the binding of Na⁺ ions to the CoroNa™ Green dye, wascaptured for ˜180 sec. thereafter. Results were expressed in relativefluorescence units (RFU) and can be determined by using the maximumsignal during the latter part of the stimulation; or the maximum minusthe minimum during the whole agonist stimulation period; or by takingthe area under the curve for the whole stimulation period.

The assay can be performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen will typically be profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

FLIPR® or FLIPR^(TETRA)® Membrane Potential Assay with KCl and TestArticle Pre-Incubation:

Cells are prepared by plating the recombinant HEK293 cells or other hostcells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of ˜40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately fewer cells andless media. The plate is then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay (see, e.g., Benjamin et. al., J. Biomol.Screen 10(4):365-373 (2005)). For screens and counter-screens of othervoltage-gated sodium channels, the assay protocol is similar, thoughoptimal densities of cells, media and subsequent assay components can befine-tuned for the particular cell line or sodium channel isoform beingtested.

The next day, at the start of the assay, the media is flicked from thecells and the wells are washed once with 50 μL/well assay buffer (1×Hank's balanced salt solution without sodium bicarbonate or phenol red,20 mM Hepes, pH 7.3) and then pre-incubated with the test articles, themembrane potential dye (for cell loading), and the KCl forre-polarization and synchronization of the channels in the entirepopulation of cells. For this dye-loading and pre-stimulation step, thecomponents are added as follows, immediately after the wash step: 1)first, the compound dilutions and controls are added as 4× concentratesin assay buffer at 50 μL/well; 2) membrane potential dye is diluted fromthe stock solution in assay buffer (4× concentrate) and added to theplate at 50 μL/well; and 3) finally, a solution of 180 mM KCl (2×) isprepared by diluting a 2M stock solution into assay buffer and thesolution added to the cells at 100 μL/well. The cells are incubated at37° C. in the dark for 30-60 mM before their fluorescence is measured.

The plates containing dye-loaded cells are then flicked to remove thepre-incubation components and washed once with 50 μL/well assay buffer.A 50 μL/well aliquot of membrane potential dye is added back to theplate, and the real-time assay is commenced. The fluorescence of cellsis measured using a fluorescence plate reader (FLIPR^(TETRA)® orFLIPR384®, MDS, Molecular Devices, Sunnyvale, Calif.). Samples areexcited by either a laser or a PMT light source (Excitationwavelength=510-545 nM) and the emissions are filtered (Emissionwavelength=565-625 nM). The additions of the compounds (first) and thenthe channel activators (later) in this are performed on the fluorescenceplate reader and the results, expressed as relative fluorescence units(RFU), are captured by means of camera shots every 1-3 sec., thendisplayed in real-time and stored. Generally, there is a 15 sec. baseline, with camera shots taken every 1.5 sec., then the test compoundsare added, then another 120 sec. baseline is conducted, with camerashots taken every 3 sec.; and finally, the agonist solution (containingveratridine and scorpion venom) is added. The amplitude of fluorescenceincrease, resulting from the detection of membrane potential change, iscaptured for ˜120 sec. thereafter. Results are expressed in relativefluorescence units (RFU) and can be determined by using the maximumsignal during the latter part of the stimulation; or the maximum minusthe minimum during the whole stimulation period; or by taking the areaunder the curve for the whole stimulation period.

The assay can be performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

FLIPR® or FLIPR^(TETRA)® Sodium Dye Assay without KCl and Test ArticlePre-Incubation:

Cells are prepared by plating the recombinant HEK293 cells or other hostcells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of 40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately fewer cells andless media. The plate is then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay. For counter-screens of other voltage-gatedsodium channels, the procedure is very similar, though optimal densitiesof cells, media and subsequent assay components can be fine-tuned forthe particular cell line or isoform.

The next day, at the start of the assay, the media is flicked from thecells and the wells washed once with 50 μL/well assay buffer (1× Hank'sbalanced salt solution without sodium bicarbonate or phenol red, 20 mMHepes, pH 7.3). Membrane potential dye is then added to each well of the96-well plate (50 μL/well), from a freshly diluted sample of the stock(now at 4× concentration) in the assay buffer. The cells are incubatedat 37° C. in the dark for 30-60 mM before their fluorescence ismeasured.

In this standard membrane potential assay, the 96-well plate containingdye-loaded cells is then loaded directly onto the plate reader withoutaspirating the dye solution and without any further washing of thecells. The fluorescence of cells is measured using a fluorescence platereader (FLIPR^(TETRA)® or FLIPR384®, MDS, Molecular Devices, Sunnyvale,Calif.). Samples are excited by either a laser or a PMT light source(Excitation wavelength=510-545 nM) and the emissions are filtered(Emission wavelength=565-625 nM). The additions of the compounds (first,50 μL/well from a 4× stock plate) and then the channel activators(later, 100 μL/well from a 2× stock solution) in this kinetic assay areperformed on the fluorescence plate reader and the results, expressed asrelative fluorescence units (RFU), are captured by means of camera shotsevery 1-3 sec., then displayed in real-time and stored. Generally, thereis a 15 sec. base line, with camera shots taken every 1.5 sec., then thetest compounds are added, then another 120 sec. baseline is conducted,with camera shots taken every 3 sec.; and finally, the agonist solution(containing veratridine and scorpion venom) is added. The amplitude offluorescence increase, resulting from the detection of membranepotential change, is captured for ˜120 sec. thereafter. Results areexpressed in relative fluorescence units (RFU) and can be determined byusing the maximum signal during the latter part of the stimulation; orthe maximum minus the minimum during the whole stimulation period; or bytaking the area under the curve for the whole stimulation period.

The assay can be performed as a screening assay as well, with the testarticles present in standard amounts (e.g. 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

Electrophysiology Assay

Cells:

The hNa_(v)1.7 expressing HEK-293 cells are plated on 35 mm culturedishes pre-coated with poly-D-lysine in standard DMEM culture media(Mediatech, Inc., Herndon, Va.) and incubated in a 5% CO₂ incubator at37° C. Cultured cells are used approximately 12-48 hours after plating.

Electrophysiology:

On the day of experimentation, the 35 mm dish is placed on the stage ofan inverted microscope equipped with a perfusion system thatcontinuously perfuses the culture dish with fresh recording media. Agravity driven superfusion system is used to apply test solutionsdirectly to the cell under evaluation. This system consists of an arrayof glass pipette connected to a motorized horizontal translator. Theoutlet of the shooter is positioned approximately 100 μm from the cellof interest.

Whole cell currents are recorded using the whole-cell patch clampconfiguration using an Axopatch 200B amplifier (Axon Instruments, FosterCity Calif.), 1322A A/D converter (Axon Instruments) and pClamp software(v. 8; Axon Instruments) and stored on a personal computer. Gigasealsare formed and the whole-cell configuration is established in voltageclamp mode, and membrane currents generated by hNa_(v)1.7 are recordedin gap-free mode. Borosilicate glass pipettes have resistance valuesbetween 1.5 and 2.0 MΩ when filled with pipette solution and seriesresistance (<5 MΩ) was compensated 75-80%. Signals are sampled at 50 kHzand low pass filtered at 3 kHz.

Voltage Protocols:

After establishing the whole-cell configuration in voltage clamp mode,voltage protocols are run to establish the 1) test potential, 2) holdingpotential, and 3) the conditioning potential for each cell.

After establishing the whole-cell configuration in voltage clamp mode, astandard I-V protocol is run to determine the potential at which themaximal current (I_(max)) is elicited. This potential is the testpotential (V_(t)). To determine a conditioning potential at which 100%of channels are in the inactivated state, a standard steady-stateinactivation (SSIN) protocol is run using a series of fifteen 100ms-long depolarizing prepulses, incrementing in 10 mV steps, immediatelyfollowed by a 5 ms testing pulse, V_(t), to V_(max). This protocol alsopermits determination of the holding potential at which all channels arein the resting state.

For compounds causing significant retardation of recovery frominactivation, an estimate of the affinity for the inactivated state ofthe channel (K_(i)) is generated using the following protocol. From thenegative, no residual inactivation, holding potential, the cell isdepolarized to the conditioning voltage for 2-5 seconds, returned to thenegative holding potential for 10-20 ms to relieve fast inactivation andthen depolarized to the test potential for ˜15 ms. This voltage protocolis repeated every 10-15 seconds, first to establish a baseline in theabsence of the test compound, then in the presence of the test compound.

After a stable baseline is established, the test compound is applied andblock of the current elicited by the test pulse assessed. In some cases,multiple cumulative concentrations are applied to identify aconcentration that blocked between 40-60% of this current. Washout ofthe compound is attempted by superfusing with control solution oncesteady-state block is observed. An estimate of the K_(i) is calculatedas follows:

K _(i)=[drug]*{FR/(1−FR)},  Eq. 1

where [drug] is the concentration of a drug, and

FR=I(after drug)/I(control),  Eq. 2

where I is the peak current amplitude. If multiple concentrations wereused, K_(i) is determined from the fit of a logistic equation to FRsplotted against corresponding drug concentrations.

In the alternative, the voltage clamp protocol to examine hNa_(v)1.7currents is as follows. First, the standard current-voltage relationshipwas tested by pulsing the cell from the holding voltage (V_(h)) of −120mV by a series of 5 msec long square-shaped test pulses incrementing in+10 mV steps over the membrane voltage range of −90 mV to +60 mV at thepace of stimulation of 0.5 Hz. This procedure determines the voltagethat elicits the maximal current (V_(max)). Second, V_(h) is re-set to−120 mV and a steady-state inactivation (SSIN) curve is taken by thestandard double-pulse protocol: 100 ms depolarizing pre-pulse wasincremented in steps of +10 mV (voltage range from −90 mV to 0 mV)immediately followed by the 5 ms long test pulse to −10 mV at the paceof stimulation of 0.2 Hz. This procedure determines the voltage of fullinactivation (V_(full)). Third, the cell is repeatedly stimulated withthe following protocol, first in the absence of the test compound thenin its presence. The protocol consists of depolarizing the cell from theholding potential of −120 mV to the V_(full) value for 4.5 seconds thenrepolarizing the cell to the holding potential for 10 ms before applyingthe test pulse to the V_(max) for 5 ms. The amount of inhibitionproduced by the test compound is determined by comparing the currentamplitude elicited by the test pulse in the absence and presence of thecompound.

In a further alternative, the voltage clamp protocol to examinehNa_(v)1.7 currents is as follows. After establishing the whole-cellconfiguration in voltage clamp mode, two voltage protocols were run toestablish: 1) the holding potential; and 2) the test potential for eachcell.

Resting Block:

To determine a membrane potential at which the majority of channels arein the resting state, a standard steady-state inactivation (SSIN)protocol is run using 100 ms prepulses×10 mV depolarizing steps. Theholding potential for testing resting block (Vh₁) is typically 20 mVmore hyperpolarized than the first potential where inactivation isobserved with the inactivation protocol.

From this holding potential a standard I-V protocol is run to determinethe potential at which the maximal current (Imax) is elicited. Thispotential is the test potential (Vt).

The compound testing protocol is a series of 10 ms depolarizations fromthe Vh₁ (determined from the SSIN) to the Vt (determined from the I-Vprotocol) repeated every 10-15 seconds. After a stable baseline isestablished, a high concentration of a test compound (highestconcentration solubility permits or that which provides 50% block) isapplied and block of the current assessed. Washout of the compound isattempted by superfusing with control solution once steady-state blockwas observed.

The fractional response is calculated as follows:

K _(r)=[drug]*{FR/(1−FR)},  Eq. 3

where [drug] is the concentration of a drug, and

FR=I(after drug)/I(control),  Eq. 2

where I is the peak current amplitude and was used for estimatingresting block dissociation constant, K_(r).

Block of Inactivated Channels:

To assess the block of inactivated channels the holding potential isdepolarized such that 20-50% of the current amplitude is reduced whenpulsed to the same Vt as above. The magnitude of this depolarizationdepends upon the initial current amplitude and the rate of current lossdue to slow inactivation. This is the second holding potential (Vh₂).The current reduction is recorded to determine the fraction of availablechannels at this potential (h).

h=I @Vh ₂ /Imax.  Eq. 4

At this membrane voltage a proportion of channels was in the inactivatedstate, and thus inhibition by a blocker includes interaction with bothresting and inactivated channels.

To determine the potency of the test compound on inactivated channels, aseries of currents are elicited by 10 ms voltage steps from Vh₂ to V_(t)every 10-15 seconds. After establishing a stable baseline, the lowconcentration of the compound is applied. In some cases, multiplecumulative concentrations will have to be applied to identify aconcentration that blocks between 40-60% of the current. Washout isattempted to re-establish baseline. Fractional responses are measuredwith respect to a projected baseline to determine K_(app).

K _(app)=[drug]*{FR/(1−FR)},  Eq. 5

where [drug] is the concentration of a drug.

This K_(app) value, along with the calculated K_(r) and h values, areused to calculate the affinity of the compound for the inactivatedchannels (K_(i)) using the following equation:

K _(i)=(1−h)/((1/K _(app))−(h/K _(r))).  Eq. 6

Solutions and Chemicals:

For electrophysiological recordings the external solution is eitherstandard, DMEM supplemented with 10 mM HEPES (pH adjusted to 7.34 withNaOH and the osmolarity adjusted to 320) or Tyrodes salt solution(Sigma, USA) supplemented with 10 mM HEPES (pH adjusted to 7.4 withNaOH; osmolarity=320). The internal pipette solution contains (in mM):NaCl (10), CsF (140), CaCl₂ (1), MgCl₂ (5), EGTA (11), HEPES (10: pH7.4, 305 mOsm). Compounds are prepared first as series of stocksolutions in DMSO and then dissolved in external solution; DMSO contentin final dilutions did not exceed 0.3%. At this concentration, DMSO doesnot affect sodium currents. Vehicle solution used to establish base linealso contains 0.3% DMSO.

Data Analysis:

Data is analyzed off-line using Clampfit software (pClamp, v.8; AxonInstruments) and graphed using GraphPad Prizm (v. 4.0) software.

In Vivo Assay for Pain

The compounds can be tested for their antinociceptive activity in theformalin model as described in Hunskaar et al., J. Neurosci. Methods 14:69-76 (1985). Male Swiss Webster NIH mice (20-30 g; Harlan, San Diego,Calif.) can be used in all experiments. Food is withdrawn on the day ofexperiment. Mice are placed in Plexiglass jars for at least 1 hour toacclimate to the environment. Following the acclimation period, mice areweighed and given either the compound of interest administered i.p. orp.o., or the appropriate volume of vehicle (for example, 10% Tween-80 or0.9% saline, and other pharmaceutically acceptable vehicles) as control.Fifteen minutes after the i.p. dosing, and 30 minutes after the p.o.dosing mice are injected with formalin (20 μL it of 5% formaldehydesolution in saline) into the dorsal surface of the right hind paw. Miceare transferred to the Plexiglass jars and monitored for the amount oftime spent licking or biting the injected paw. Periods of licking andbiting are recorded in 5-minute intervals for 1 hour after the formalininjection. All experiments are done in a blinded manner during the lightcycle.

The early phase of the formalin response is measured as licking/bitingbetween 0-5 minutes, and the late phase is measured from 15-50 minutes.Differences between vehicle and drug treated groups can be analyzed byone-way analysis of variance (ANOVA). A P value<0.05 is consideredsignificant. Compounds are considered to be efficacious for treatingacute and chronic pain if they have activity in blocking both the earlyand second phase of formalin-induced paw-licking activity.

In Vivo Assays for Inflammatory or Neuropathic Pain

Test Animals:

Each experiment uses rats weighing between 200-260 g at the start of theexperiment. The rats are group-housed and have free access to food andwater at all times, except prior to oral administration of a testcompound when food is removed for 16 hours before dosing. A controlgroup acts as a comparison to rats treated with a Compound of theInvention. The control group is administered the carrier as used for thetest compound. The volume of carrier administered to the control groupis the same as the volume of carrier and test compound administered tothe test group.

Inflammatory Pain:

To assess the actions of the compounds of Formulae I-V on the treatmentof inflammatory pain the Freund's complete adjuvant (“FCA”) model ofinflammatory pain is used. FCA-induced inflammation of the rat hind pawis associated with the development of persistent inflammatory mechanicaland thermal hyperalgesia and provides reliable prediction of theanti-hyperalgesic action of clinically useful analgesic drugs (Bartho etal., Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670 (1990)).The left hind paw of each animal is administered a 50 μL intraplantarinjection of 50% FCA. 24 hour post injection, the animal is assessed forresponse to noxious mechanical stimuli by determining the paw withdrawalthreshold (PWT), or to noxious thermal stimuli by determining the pawwithdrawal latency (PWL), as described below. Rats are then administereda single injection of either a test compound or 30 mg/Kg of a positivecontrol compound (indomethacin). Responses to noxious mechanical orthermal stimuli are then determined 1, 3, 5 and 24 hours postadministration (admin).

Percentage reversal of hyperalgesia for each animal is defined as:

${\% \mspace{14mu} {reversal}} = {\frac{\begin{bmatrix}{\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right)\end{bmatrix}}{\begin{bmatrix}{\left( {{baseline}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right)\end{bmatrix}} \times 100}$

Neuropathic Pain:

To assess the actions of the test compounds for the treatment ofneuropathic pain the Seltzer model or the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats(Seltzer et al., Pain 43:205-218 (1990)). Partial ligation of the leftsciatic nerve is performed under isoflurane/O₂ inhalation anesthesia.Following induction of anesthesia, the left thigh of the rat is shavedand the sciatic nerve exposed at high thigh level through a smallincision and is carefully cleared of surrounding connective tissues at asite near the trocanther just distal to the point at which the posteriorbiceps semitendinosus nerve branches off of the common sciatic nerve. A7-0 silk suture is inserted into the nerve with a 38 curved,reversed-cutting mini-needle and tightly ligated so that the dorsal ⅓ to½ of the nerve thickness is held within the ligature. The wound isclosed with a single muscle suture (4-0 nylon (Vicryl)) and vetbondtissue glue. Following surgery, the wound area is dusted with antibioticpowder. Sham-treated rats undergo an identical surgical procedure exceptthat the sciatic nerve is not manipulated. Following surgery, animalsare weighed and placed on a warm pad until they recover from anesthesia.Animals are then returned to their home cages until behavioral testingbegins.

The animals are assessed for response to noxious mechanical stimuli bydetermining PWT, as described below, prior to surgery (baseline), thenimmediately prior to and 1, 3, and 5 hours after drug administration forrear paw of the animal. Percentage reversal of neuropathic hyperalgesiais defined as:

${\% \mspace{14mu} {reversal}} = {\frac{\begin{bmatrix}{\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)\end{bmatrix}}{\begin{bmatrix}{\left( {{baseline}\mspace{14mu} {PWT}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)\end{bmatrix}} \times 100}$

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anesthesia. Following induction of anesthesia a 3 cm incisionis made and the left paraspinal muscles are separated from the spinousprocess at the L₄-S₂ levels. The L₆ transverse process is carefullyremoved with a pair of small rongeurs to identify visually the L₄-L₆spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) is (are)isolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is (are)not manipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then returned totheir home cages until behavioral testing begins.

The animals are assessed for response to noxious mechanical stimuli bydetermining PWT, as described below, prior to surgery (baseline), thenimmediately prior to and 1, 3, and 5 hours after being administered aCompound of the Invention for the left rear paw of the animal. Theanimals can also be assessed for response to noxious thermal stimuli orfor tactile allodynia, as described below. The Chung model forneuropathic pain is described in Kim et al., Pain 50(3):355-363 (1992).

Tactile Allodynia:

Sensitivity to non-noxious mechanical stimuli can be measured in animalsto assess tactile allodynia. Rats are transferred to an elevated testingcage with a wire mesh floor and allowed to acclimate for five to tenminutes. A series of von Frey monofilaments are applied to the plantarsurface of the hindpaw to determine the animal's withdrawal threshold.The first filament used possesses a buckling weight of 9.1 gms (0.96 logvalue) and is applied up to five times to see if it elicits a withdrawalresponse. If the animal has a withdrawal response, then the nextlightest filament in the series would be applied up to five times todetermine if it also could elicit a response. This procedure is repeatedwith subsequent lesser filaments until there is no response and theidentity of the lightest filament that elicits a response is recorded.If the animal does not have a withdrawal response from the initial 9.1gms filament, then subsequent filaments of increased weight are applieduntil a filament elicits a response and the identity of this filament isrecorded. For each animal, three measurements are made at every timepoint to produce an average withdrawal threshold determination. Testscan be performed prior to, and at 1, 2, 4 and 24 hours post drugadministration.

Mechanical Hyperalgesia:

Sensitivity to noxious mechanical stimuli can be measured in animalsusing the paw pressure test to assess mechanical hyperalgesia. In rats,hind paw withdrawal thresholds (“PWT”), measured in grams, in responseto a noxious mechanical stimulus are determined using an analgesymeter(Model 7200, commercially available from Ugo Basile of Italy), asdescribed in Stein (Biochemistry & Behavior 31: 451-455 (1988)). Therat's paw is placed on a small platform, and weight is applied in agraded manner up to a maximum of 250 grams. The endpoint is taken as theweight at which the paw is completely withdrawn. PWT is determined oncefor each rat at each time point. PWT can be measured only in the injuredpaw, or in both the injured and non-injured paw. In one non-limitingembodiment, mechanical hyperalgesia associated with nerve injury inducedpain (neuropathic pain) can be assessed in rats. Rats are tested priorto surgery to determine a baseline, or normal, PWT. Rats are testedagain 2 to 3 weeks post-surgery, prior to, and at different times after(e.g. 1, 3, 5 and 24 hr) drug administration. An increase in PWTfollowing drug administration indicates that the test compound reducesmechanical hyperalgesia.

In Vivo Assay for Anticonvulsant Activity

Compounds of the Invention can be tested for in vivo anticonvulsantactivity after i.v., p.o., or i.p. injection using any of a number ofanticonvulsant tests in mice, including the maximum electroshock seizuretest (MES). Maximum electroshock seizures are induced in male NSA miceweighing between 15-20 g and in male Sprague-Dawley rats weighingbetween 200-225 g by application of current (for mice: 50 mA, 60pulses/sec, 0.8 msec pulse width, 1 sec duration, D.C.; for rats: 99 mA,125 pulses/sec, 0.8 msec pulse width, 2 sec duration, D.C.) using a UgoBasile ECT device (Model 7801). Mice are restrained by gripping theloose skin on their dorsal surface and saline-coated corneal electrodesare held lightly against the two corneae. Rats are allowed free movementon the bench top and ear-clip electrodes are used. Current is appliedand animals are observed for a period of up to 30 seconds for theoccurrence of a tonic hindlimb extensor response. A tonic seizure isdefined as a hindlimb extension in excess of 90 degrees from the planeof the body. Results can be treated in a quantal manner.

Pharmaceutical Compositions

Although a Compound of the Invention can be administered to a mammal inthe form of a raw chemical without any other components present, thecompound is preferably administered as part of a pharmaceuticalcomposition containing the compound combined with a suitablepharmaceutically acceptable carrier. Such a carrier can be selected frompharmaceutically acceptable excipients and auxiliaries.

Pharmaceutical compositions within the scope of the invention includeall compositions where a Compound of the Invention is combined with apharmaceutically acceptable carrier. In one embodiment, the compound ispresent in the composition in an amount that is effective to achieve itsintended therapeutic purpose. While individual needs may vary, adetermination of optimal ranges of effective amounts of each compound iswithin the skill of the art.

Typically, a compound can be administered to a mammal, e.g., a human,orally at a dose of from about 0.0025 to about 1500 mg per kg bodyweight of the mammal, or an equivalent amount of a pharmaceuticallyacceptable salt, hydrate, diastereomer, or solvate thereof, per day totreat the particular disorder. A useful oral dose of a Compound of theInvention administered to a mammal is from about 0.0025 to about 50 mgper kg body weight of the mammal, or an equivalent amount of thepharmaceutically acceptable salt, hydrate, diastereomer, or solvatethereof. For intramuscular injection, the dose is typically aboutone-half of the oral dose.

A unit oral dose may comprise from about 0.01 to about 50 mg, andpreferably about 0.1 to about 10 mg, of the compound. The unit dose canbe administered one or more times daily, e.g., as one or more tablets orcapsules, each containing from about 0.01 to about 50 mg of thecompound, or an equivalent amount of a pharmaceutically acceptable salt,hydrate, diastereomer, or solvate thereof.

A pharmaceutical composition of the invention can be administered to anyanimal that may experience the beneficial effects of a Compound of theInvention. Foremost among such animals are mammals, e.g., humans andcompanion animals, although the invention is not intended to be solimited.

A pharmaceutical composition of the invention can be administered by anymeans that achieves its intended purpose. For example, administrationcan be by the oral, parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, intranasal, transmucosal,rectal, intravaginal or buccal route, or by inhalation. The dosageadministered and route of administration will vary, depending upon thecircumstances of the particular subject, and taking into account suchfactors as age, gender, health, and weight of the recipient, conditionor disorder to be treated, kind of concurrent treatment, if any,frequency of treatment, and the nature of the effect desired.

In one embodiment, a pharmaceutical composition of the invention can beadministered orally and is formulated into tablets, dragees, capsules oran oral liquid preparation. In one embodiment, the oral formulationcomprises extruded multiparticulates comprising the Compound of theInvention.

Alternatively, a pharmaceutical composition of the invention can beadministered rectally, and is formulated in suppositories.

Alternatively, a pharmaceutical composition of the invention can beadministered by injection.

Alternatively, a pharmaceutical composition of the invention can beadministered transdermally.

Alternatively, a pharmaceutical composition of the invention can beadministered by inhalation or by intranasal or transmucosaladministration.

Alternatively, a pharmaceutical composition of the invention can beadministered by the intravaginal route.

A pharmaceutical composition of the invention can contain from about0.01 to 99 percent by weight, and preferably from about 0.25 to 75percent by weight, of active compound(s).

A method of the invention, such as, a method for treating a disorderresponsive to the blockade of one or more sodium channels in an animalin need thereof, can further comprise administering a second therapeuticagent to the animal in combination with a Compound of the Invention. Inone embodiment, the other therapeutic agent is administered in aneffective amount.

Effective amounts of the other therapeutic agents are known to thoseskilled in the art. However, it is well within the skilled artisan'spurview to determine the other therapeutic agent's optimaleffective-amount range.

A Compound of the Invention (i.e., the first therapeutic agent) and thesecond therapeutic agent can act additively or, in one embodiment,synergistically. Alternatively, the second therapeutic agent can be usedto treat a disorder or condition that is different from the disorder orcondition for which the first therapeutic agent is being administered,and which disorder or condition may or may not be a condition ordisorder as defined herein.

In one embodiment, a Compound of the Invention is administeredconcurrently with a second therapeutic agent; for example, a singlecomposition comprising both an effective amount of a Compound of theInvention, and an effective amount of the second therapeutic agent canbe administered.

Accordingly, the invention further provides a pharmaceutical compositioncomprising a combination of a Compound of the Invention, the secondtherapeutic agent, and a pharmaceutically acceptable diluent or carrier.

Alternatively, a first pharmaceutical composition comprising aneffective amount of a Compound of the Invention and a secondpharmaceutical composition comprising an effective amount of the secondtherapeutic agent can be concurrently administered.

In another embodiment, an effective amount of a Compound of theInvention is administered prior or subsequent to administration of aneffective amount of the second therapeutic agent. In this embodiment,the Compound of the Invention is administered while the secondtherapeutic agent exerts its therapeutic effect, or the secondtherapeutic agent is administered while the Compound of the Inventionexerts its therapeutic effect for treating a disorder or condition.

The second therapeutic agent can be an opioid agonist, a non-opioidanalgesic, a non-steroidal anti-inflammatory agent, an antimigraineagent, a Cox-II inhibitor, a β-adrenergic blocker, an anticonvulsant, anantidepressant, an anticancer agent, an agent for treating addictivedisorder, an agent for treating Parkinson's disease and parkinsonism, anagent for treating anxiety, an agent for treating epilepsy, an agent fortreating a seizure, an agent for treating a stroke, an agent fortreating a pruritic condition, an agent for treating psychosis, an agentfor treating ALS, an agent for treating a cognitive disorder, an agentfor treating a migraine, an agent for treating vomiting, an agent fortreating dyskinesia, or an agent for treating depression, or a mixturethereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable salts thereof, and mixturesthereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable saltsthereof, and mixtures thereof.

Examples of useful non-opioid analgesics include non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable salts thereof, and mixtures thereof.Examples of other suitable non-opioid analgesics include the following,non limiting, chemical classes of analgesic, antipyretic, nonsteroidalantiinflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; paraaminophennol derivatives including acetaminophen and phenacetin; indoleand indene acetic acids, including indomethacin, sulindac, and etodolac;heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac;anthranilic acids (fenamates), including mefenamic acid, andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Inset, Analgesic Antipyretic andAntiinflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed 1996) and Glen R.Hanson, Analgesic, Antipyretic and Anti Inflammatory Drugs in Remington:The Science and Practice of Pharmacy Vol. II 1196-1221 (A. R. Gennaroed. 19th ed. 1995) which are hereby incorporated by reference in theirentireties. Suitable Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox II inhibitors include, but are not limited to, rofecoxib andcelecoxib.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, and mixtures thereof.

Examples of useful β-adrenergic blockers include, but are not limitedto, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol,betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol,bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol,carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol,dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol,mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol,nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol,practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol,tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenyloin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenyloin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

Examples of useful antidepressants include, but are not limited to,binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan,fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

Examples of useful anticancer agents include, but are not limited to,acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, altretamine, ambomycin, ametantrone acetate,aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa,bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin,bleomycin sulfate, brequinar sodium, bropirimine, busulfan,cactinomycin, calusterone, caracemide, carbetimer, carboplatin,carmustine, carubicin hydrochloride, carzelesin, cedefingol,chlorambucil, cirolemycin, and cisplatin.

Therapeutic agents useful for treating an addictive disorder include,but are not limited to, methadone, desipramine, amantadine, fluoxetine,buprenorphine, an opiate agonist, 3-phenoxypyridine, or a serotoninantagonist.

Examples of useful therapeutic agents for treating Parkinson's diseaseand parkinsonism include, but are not limited to, carbidopalevodopa,pergolide, bromocriptine, ropinirole, pramipexole, entacapone,tolcapone, selegiline, amantadine, and trihexyphenidyl hydrochloride.

Examples of useful therapeutic agents for treating anxiety include, butare not limited to, benzodiazepines, such as alprazolam, brotizolam,chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam,diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam,midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam,temazepam, and triazolam; non-benzodiazepine agents, such as buspirone,gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, and zaleplon;tranquilizers, such as barbituates, e.g., amobarbital, aprobarbital,butabarbital, butalbital, mephobarbital, methohexital, pentobarbital,phenobarbital, secobarbital, and thiopental; and propanediol carbamates,such as meprobamate and tybamate.

Examples of useful therapeutic agents for treating epilepsy or seizureinclude, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, benzodiazepines, gamma-vinyl GABA, acetazolamide,and felbamate.

Examples of useful therapeutic agents for treating stroke include, butare not limited to, anticoagulants such as heparin, agents that break upclots such as streptokinase or tissue plasminogen activator, agents thatreduce swelling such as mannitol or corticosteroids, and acetylsalicylicacid.

Examples of useful therapeutic agents for treating a pruritic conditioninclude, but are not limited to, naltrexone; nalmefene; danazol;tricyclics such as amitriptyline, imipramine, and doxepin;antidepressants such as those given below; menthol; camphor; phenol;pramoxine; capsaicin; tar; steroids; and antihistamines.

Examples of useful therapeutic agents for treating psychosis include,but are not limited to, phenothiazines such as chlorpromazinehydrochloride, mesoridazine besylate, and thoridazine hydrochloride;thioxanthenes such as chloroprothixene and thiothixene hydrochloride;clozapine; risperidone; olanzapine; quetiapine; quetiapine fumarate;haloperidol; haloperidol decanoate; loxapine succinate; molindonehydrochloride; pimozide; and ziprasidone.

Examples of useful therapeutic agents for treating ALS include, but arenot limited to, baclofen, neurotrophic factors, riluzole, tizanidine,benzodiazepines such as clonazepan and dantrolene.

Examples of useful therapeutic agents for treating cognitive disordersinclude, but are not limited to, agents for treating dementia such astacrine; donepezil; ibuprofen; antipsychotic drugs such as thioridazineand haloperidol; and antidepressant drugs such as those given below.

Examples of useful therapeutic agents for treating a migraine include,but are not limited to, sumatriptan; methysergide; ergotamine; caffeine;and beta-blockers such as propranolol, verapamil, and divalproex.

Examples of useful therapeutic agents for treating vomiting include, butare not limited to, 5-HT3 receptor antagonists such as ondansetron,dolasetron, granisetron, and tropisetron; dopamine receptor antagonistssuch as prochlorperazine, thiethylperazine, chlorpromazine,metoclopramide, and domperidone; glucocorticoids such as dexamethasone;and benzodiazepines such as lorazepam and alprazolam.

Examples of useful therapeutic agents for treating dyskinesia include,but are not limited to, reserpine and tetrabenazine.

Examples of useful therapeutic agents for treating depression include,but are not limited to, tricyclic antidepressants such as amitryptyline,amoxapine, bupropion, clomipramine, desipramine, doxepin, imipramine,maprotiline, nefazadone, nortriptyline, protriptyline, trazodone,trimipramine, and venlafaxine; selective serotonin reuptake inhibitorssuch as citalopram, (S)-citalopram, fluoxetine, fluvoxamine, paroxetine,and setraline; monoamine oxidase inhibitors such as isocarboxazid,pargyline, phenelzine, and tranylcypromine; and psychostimulants such asdextroamphetamine and methylphenidate.

A pharmaceutical composition of the invention is manufactured in amanner which itself will be known in view of the instant disclosure, forexample, by means of conventional mixing, granulating, dragee-making,dissolving, extrusion, or lyophilizing processes. Thus, pharmaceuticalcompositions for oral use can be obtained by combining the activecompound with solid excipients, optionally grinding the resultingmixture and processing the mixture of granules, after adding suitableauxiliaries, if desired or necessary, to obtain tablets or dragee cores.

In addition to a Compound (or Compounds) of the Invention, apharmaceutical composition of the invention may contain inert diluentscommonly used in the art, such as, water or other solvents, solubilizingagents and emulsifiers, such as, ethyl alcohol, isopropyl alcohol,1,3-butylene glycol, oils (e.g., cottonseed, groundnut, corn, germ,olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol,polyethylene glycols, and fatty acid esters of sorbitan, and mixturesthereof.

Suitable excipients include fillers such as saccharides (for example,lactose, sucrose, mannitol or sorbitol), cellulose preparations, calciumphosphates (for example, tricalcium phosphate or calcium hydrogenphosphate), as well as binders such as starch paste (using, for example,maize starch, wheat starch, rice starch, or potato starch), gelatin,tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one ormore disintegrating agents can be added, such as the above-mentionedstarches and also carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodiumalginate.

Auxiliaries are typically flow-regulating agents and lubricants such as,for example, silica, talc, stearic acid or salts thereof (e.g.,magnesium stearate or calcium stearate), and polyethylene glycol. Drageecores are provided with suitable coatings that are resistant to gastricjuices. For this purpose, concentrated saccharide solutions can be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations such as acetylcellulose phthalate orhydroxypropymethyl-cellulose phthalate can be used. Dye stuffs orpigments can be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Examples of other pharmaceutical preparations that can be used orallyinclude push-fit capsules made of gelatin, or soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain a compound in the form of granules, which can bemixed with fillers such as lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizers, or in the form of extruded multiparticulates. In softcapsules, the active compounds are preferably dissolved or suspended insuitable liquids, such as fatty oils or liquid paraffin. In addition,stabilizers can be added.

Possible pharmaceutical preparations for rectal administration include,for example, suppositories, which consist of a combination of one ormore active compounds with a suppository base. Suitable suppositorybases include natural and synthetic triglycerides, and paraffinhydrocarbons, among others. It is also possible to use gelatin rectalcapsules consisting of a combination of active compound with a basematerial such as, for example, a liquid triglyceride, polyethyleneglycol, or paraffin hydrocarbon.

Suitable formulations for parenteral administration include aqueoussolutions of the active compound in a water-soluble form such as, forexample, a water-soluble salt, alkaline solution, or acidic solution.Alternatively, a suspension of the active compound can be prepared as anoily suspension. Suitable lipophilic solvents or vehicles for such assuspension may include fatty oils (for example, sesame oil), syntheticfatty acid esters (for example, ethyl oleate), triglycerides, or apolyethylene glycol such as polyethylene glycol-400 (PEG-400). Anaqueous suspension may contain one or more substances to increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran. The suspension mayoptionally contain stabilizers.

The following examples are illustrative, but not limiting, of thecompounds, compositions and methods of the invention. Suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art in view of this disclosure arewithin the spirit and scope of the invention.

EXAMPLES Example 1 Synthesis ofN¹-(4-(4-fluorophenoxy)phenyl)benzene-1,2-diamine (Compound 7)

A mixture of 1-fluoro-4-nitrobenzene (Compound 1) (38 g, 0.27 mol),4-fluorophenol (Compound 2) (30 g, 0.27 mol) and K₂CO₃ (37.8 g, 0.27mol) in DMF (300 mL) was heated at 95° C. for 20 h. The reaction mixturewas cooled to RT and diluted with EtOAc (150 mL). The organic layer waswashed with water, dried over MgSO₄ and concentrated. The residue waspurified by flash chromatography (SiO₂, 5% EtOA/chexanes) to giveCompound 3 as brown crystals (44 g, 70% yield). ¹H NMR (400 MHz, CDCl₃):δ 8.20 (d, J=9.4 Hz, 2H), 7.04-7.17 (m, 4H), 6.99 (d, J=9.4, 2H).

Compound 3 (23.3 g, 0.1 mol) was dissolved in MeOH (50 mL) and 5% Pd/C(50 mg) was added. The reaction mixture was hydrogenated at RT under aballoon of hydrogen for 16 h. The reaction mixture was filtered throughCelite and the filtrate concentrated to give Compound 4 as an off-whitesolid (20.4 g, 100% yield). LC/MS: m/z=204.3 [M+H]⁺ (Calc: 203.2).

A mixture of Compound 4 (1.02 g, 5.0 mmol), 1-fluoro-2-nitrobenzene(Compound 5) (0.71 g, 5.0 mmol) and DIPEA (1 mL) in DMSO (2 mL) washeated at 150° C. in a microwave reactor (Milestone MicroSYNTH) for 2 h.After cooling to RT the reaction mixture was diluted with water andextracted with DCM (3×100 mL). The combined organic layers were driedover Na₂SO₄, concentrated and the residue purified by flashchromatography (SiO₂, 5% MeOH/DCM) to give Compound 6 (1.38 g, 85%yield). LC/MS: m/z=325.2 [M+H]⁺ (Calc: 324.3).

Compound 6 (3.6 g, 11.1 mol) was dissolved in a mixture of MeOH (60 mL)and DCM (20 mL), 10% Pd/C (360 mg) was added and the mixturehydrogenated at RT at 50 psi of hydrogen for 3 h. The reaction mixturewas filtered through Celite and the filtrate concentrated to giveCompound 7 as an off-white solid (2.94 g, 90% yield). This material wasof adequate purity for subsequent reactions. LC/MS: m/z=295.2 [M+H]⁺(Calc: 294.3).

Example 21-(4-(4-Fluorophenoxy)phenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole(Compound 9)

To a solution of Compound 7 (147.2 mg, 0.5 mmol) in EtOH (1 mL) wasadded Compound 8 (57.1 mg, 0.5 mmol) and 40% aq. NaHSO₃ (1.1 mL) at RT.The reaction mixture was heated at 150° C. in a microwave reactor for 30min. After cooling to RT the reaction mixture was diluted water andextracted with DCM (3×100 mL). The combined organic layers were driedover Na₂SO₄, concentrated and the residue purified by flashchromatography (SiO₂, 0-15% MeOH/DCM) to give Compound 9 (97 mg, 50%yield): ¹H NMR (400 MHz, CD₃OD): δ 7.58 (d, J=8.0 Hz, 1H), 7.35 (m, 2H),7.18 (m, 1H), 7.14-7.08 (m, 7H), 6.99 (d, J=8.0 Hz, 1H), 3.89 (m, 2H),3.31 (m, 2H), 2.99 (m, 1H), 1.98 (m, 1H), 1.71 (m, 2H). LC/MS: m/z=389.2[M+H]⁺ (Calc: 388.4).

In a similar manner, the following compounds were prepared:

2-(4-Chloro-1-methyl-1H-pyrazol-3-yl)-1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazole(Compound 10): ¹H NMR (400 MHz, CD₃OD): δ 7.81 (m, 2H), 7.44-7.31 (m,5H), 7.20-7.05 (m, 6H), 3.88 (s, 3H). LC/MS: m/z=419.1 [M+H]⁺ (Calc:418.9).

1-(4-(4-fluorophenoxy)phenyl)-2-(1H-imidazol-4-yl)-1H-benzo[d]imidazole(Compound 11): ¹H NMR (400 MHz, CD₃OD): δ 7.73 (m, 2H), 7.41 (m, 2H),7.32 (m, 3H), 7.19 (m, 7H). LC/MS: m/z=371.1 [M+H]⁺ (Calc: 370.4).

Example 3(S)-5-(1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(Compound 14)

To a mixture of Compound 7 (200 mg, 0.68 mmol) and Compound 12 (88 mg,0.68 mmol) in DCM (10 mL) was added HOBt (135 mg, 1.0 mmol), EDCI (192mg, 1.0 mmol) and DIPEA (0.4 mL) at RT. The reaction mixture was stirredat RT for 16 h, quenched by the addition of water and extracted withDCM. The combined organic layers were dried over Na₂SO₄, concentratedand the residue purified by flash chromatography (SiO₂, 0-15% MeOH/DCM)to give Compound 13 (200 mg, 72% yield). LC/MS: m/z=406.3 [M+H]⁺ (Calc:405.4).

A mixture of Compound 13 (200 mg, 0.49 mmol) and AcOH (0.4 mL) intoluene (10 mL) was heated at 160° C. in a microwave reactor for 1 h.After cooling to RT, the reaction was quenched by the addition of satd.aq. NaHCO₃ and the mixture extracted with DCM. The combined organiclayers were dried over Na₂SO₄, concentrated and the residue purified byflash chromatography (SiO₂, 30% (10% NH₄OH in MeOH) in DCM) to giveCompound 14 (143 mg, 75% yield). ¹H NMR (400 MHz, CD₃OD): δ 7.73 (m,1H), 7.49 (m, 2H), 7.32 (m, 2H), 7.26-7.13 (m, 7H), 4.97 (m, 1H),2.57-2.31 (m, 4H). LC/MS: m/z=388.2 [M+H]⁺ (Calc: 387.4).

In a similar manner, the following compounds were prepared:

2-((1H-tetrazol-5-yl)methyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazole(Compound 15): ¹H NMR (400 MHz, CD₃OD): δ 7.61 (m, 1H), 7.48 (m, 2H),7.21 (m, 4H), 7.12 (m, 5H), 4.49 (s, 2H). LC/MS: m/z=387.1 [M+H]⁺ (Calc:386.4).

1-(4-(4-Fluorophenoxy)phenyl)-2-((5-methyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole(Compound 16): ¹H NMR (400 MHz, CD₃OD): δ 7.68 (m, 1H), 7.41 (m, 2H),7.29 (m, 2H), 7.23-7.10 (m, 7H), 4.28 (br, 2H), 2.36 (s, 3H). LC/MS:m/z=400.2 [M+H]⁺ (Calc: 399.4).

1-(4-(4-Fluorophenoxy)phenyl)-2-(2-(piperidin-1-yl)ethyl)-1H-benzo[d]imidazole(Compound 17): ¹H NMR (400 MHz, CD₃OD): δ 7.66 (m, 1H), 7.48 (m, 2H),7.33-7.12 (m, 9H), 3.03 (m, 2H), 2.79 (m, 2H), 2.41 (br, 4H), 1.57 (m,4H), 1.45 (m, 2H). LC/MS: m/z=416.2 [M+H]⁺ (Calc: 415.5).

tert-Butyl(S)-2-(1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(Compound 18): LC/MS: m/z=47.2 [M+H]⁺ (Calc: 473.5).

tert-Butyl4-(1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate(Compound 19): LC/MS: m/z=488.4 [M+H]⁺ (Calc: 487.6).

Example 4 Synthesis of1-(4-(4-fluorophenoxy)phenyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole(Compound 20)

To a solution of Compound 19 (300 mg, 0.61 mmol) in MeOH (4 mL) wasadded 4N HCl in dioxane (4 mL, 16 mmol), the mixture stirred at RT for 2h and concentrated. The crude Compound 20 was used without furtherpurification. LC/MS: m/z=388.3 [M+H]⁺ (Calc: 387.5).

In a similar manner, the following compound was prepared:

(S)-1-(4-(4-fluorophenoxy)phenyl)-2-(pyrrolidin-2-yl)-1H-benzo[d]imidazole(Compound 21): LC/MS: m/z=374.2 [M+H]⁺ (Calc: 373.4).

Example 52-(4-(1-(4-(4-Fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)acetamide(Compound 23)

A mixture of Compound 20 (155 mg, 0.4 mmol) and Compound 22 (83 mg, 0.6mmol) in DMF (4 mL) was stirred at 70 C for 2 h. The reaction mixturewas cooled to RT, concentrated and the residue purified by flashchromatography (SiO₂, 10% (10% NH₄OH in MeOH) in DCM) to give Compound23 (100 mg, 56% yield). ¹H NMR (400 MHz, CD₃OD): δ 7.70 (d, J=8 Hz, 1H),7.45 (m, 2H), 7.34-7.18 (m, 8H), 7.10 (m, 1H), 2.98 (m, 4H), 2.79 (m,1H), 2.15 (m, 4H), 1.90 (m, 2H). LC/MS: m/z=445.2 [M+H]⁺ (Calc: 444.5).

In a similar manner, the following compounds were prepared:

N,N-diethyl-2-(4-(1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)acetamide(Compound 24): ¹H NMR (400 MHz, CD₃OD): δ 7.57 (m, 1H), 7.33 (m, 2H),7.21-7.05 (m, 8H), 6.99 (m, 1H), 3.39 (m, 2H), 3.27 (m, 2H), 3.09 (s,2H), 2.87 (m, 2H), 2.70 (m, 1H), 1.97 (m, 4H), 1.79 (m, 2H), 1.15 (m,3H), 1.01 (m, 3H). LC/MS: m/z=501.3 [M+H]⁺ (Calc: 500.6).

(S)-2-(2-(1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)acetamide(Compound 25): ¹H NMR (400 MHz, CD₃OD): δ 7.61 (m, 1H), 7.33 (m, 2H),7.26-7.05 (m, 8H), 7.01 (m, 1H), 3.75 (m, 1H), 3.16 (m, 2H), 2.77 (m,1H), 2.34 (m, 1H), 2.15-1.87 (m, 3H), 1.78 (m, 1H). LC/MS: m/z=431.3[M+H]⁺ (Calc: 430.5).

Example 6

In similar manners as those delineated in EXAMPLES 1-5, the followingcompounds were prepared:

2-((1-(1-(4-(4-(Trifluoromethyl)-phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)acetamide(Compound 27): LC/MS: m/z=455.1 [M+H]⁺ (Calc: 454.2).

3-Hydroxy-2-(((1-(4-(4-(trifluoro-methyl)phenoxy)phenyl)-1H-benzo-[d]imidazol-2-yl)methyl)amino)propanamide(Compound 30): LC/MS: m/z=471.1 [M+H]⁺ (Calc: 470.2).

1-((1-(4-(4-(Trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)pyrrolidine-2-carboxamide(Compound 33): LC/MS: m/z=481.2 [M+H]⁺ (Calc: 480.2).

5-Oxo-1-((1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)-pyrrolidine-2-carboxylicacid (Compound 42): LC/MS: m/z=496.0 [M+H]⁺ (Calc: 495.1).

5-Oxo-1-((1-(4-(4-(trifluoro-methyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)-pyrrolidine-2-carboxamide(Compound 43): LC/MS: m/z=495.1 [M+H]⁺ (Calc: 494.2).

Likewise, Compound Nos. 26, 28, 29, 31, 32, and 34 to 41 can besimilarly prepared.

Example 7

Representative compounds of the invention have been tested in the FLIPR®or FLIPR^(TETRA)® sodium dye assay with KCl assay for sodium channelblocking activity, which is described in detail above. Representativevalues are presented in TABLE 3.

TABLE 3 Evaluation of compounds as sodium channel (Na_(v)) blockersNa_(v)1.7 Activity (μM) FLIPR assay Compound No. IC₅₀ (μM) ± SEM 9 0.630± 0.050 10 0.313 ± 0.032 11 0.102 ± 0.022 14 0.571 ± 0.070 16 0.957 ±0.092 17 0.081 ± 0.009 15 >20 24 0.516 ± 0.029 23 1.493 ± 0.225 25 1.221± 0.035

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents and publications cited herein are fully incorporated byreference herein in their entirety.

1. A compound of Formula I, or a pharmaceutically acceptable salt,solvate, hydrate, or diastereomer thereof:

Wherein m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, or 4; Each of W¹,W², W³, and W⁴, independently, is C(R³) or N, provided that at least oneof W¹, W², W³, and W⁴ is C(R³); G is H, alkyl, alkoxy, amino, amide,aryl, cycloalkyl, R⁶OC(O)—, R⁶C(O)O—, (R⁶)₂NC(O)O—, heterocyclyl,heteroaryl, or sulfonamide, wherein each of the alkyl, alkoxy, amino,amide, aryl, cycloalkyl, heterocyclyl, heteroaryl, R⁶OC(O)—, R⁶C(O)O—,(R⁶)₂NC(O)O—, and sulfonamide is optionally substituted; U isoptionally-substituted naphthyl or

Each of Z¹, Z², Z³, Z⁴, and Z⁵, independently, is CH or N, provided thatat most three of Z¹, Z², Z³, Z⁴, and Z⁵ can be N at the same time; —Y—Xis selected from the group consisting of a) —O—(C₀₋₃)alkyl-X, which isoptionally substituted; b) —(C₀₋₃)alkyl-S—X, which is optionallysubstituted; c) —S—(C₁₋₃)alkyl-X, which is optionally substituted; d)—(C₀₋₃)alkyl-S(O)—X, which is optionally substituted; e)—S(O)—(C₁₋₃)alkyl-X, which is optionally substituted; f)—(C₀₋₃)alkyl-S(O)₂—X, which is optionally substituted; g)—S(O)₂(C₁₋₃)alkyl-X, which is optionally substituted; h)—(C₁₋₃)alkyl-N(R⁵)—X, which is optionally substituted; i)—(C₁₋₃)alkyl-N(R⁵)C(O)—X, which is optionally substituted; j)—(C₁₋₃)alkyl-C(O)N(R⁵)—X, which is optionally substituted; and l)—(C₁₋₆)alkyl-X, which is optionally substituted; X isoptionally-substituted aryl or optionally-substituted heteroaryl; E is abond or carbonyl; R¹ and R², each independently, are H, alkyl, amide,amino, cyano, alkoxy, hydroxyl, halogen, cycloalkyl, aryl, heteroaryl,or heterocyclyl, wherein each of the alkyl, alkoxy, amide, amino,cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionallysubstituted; R³ and R⁴, each independently, are H, alkyl, alkoxy, amide,amino, R⁶OC(O)—, R⁶C(O)O—, (R⁶)₂NC(O)O—, cyano, cycloalkyl,heterocyclyl, hydroxyl, halogen, sulfonamide, or nitro, wherein each ofsaid alkyl, alkoxy, amide, amino, R⁶OC(O)—, R⁶C(O)O—, (R⁶)₂NC(O)O—,cycloalkyl, heterocyclyl, and sulfonamide groups is optionallysubstituted; R⁵, on each occurrence, independently is H, alkyl,cycloalkyl, heterocyclyl, (alkyl)carbonyl, or (amino)carbonyl, whereineach of the alkyl, cycloalkyl, heterocyclyl, (alkyl)carbonyl, and(amino)carbonyl is optionally substituted; R⁶, on each occurrence,independently is H, alkyl, aryl, cycloalkyl, heteroaryl, orheterocyclyl, wherein each of said alkyl, aryl, cycloalkyl, heteroaryl,and heterocyclyl is optionally substituted; provided that i) when U is

and —Y—X is —O—CH₂—X, then X is further substituted by a group otherthan H; ii) when U is

and —Y—X is —O—X, then G is alkoxy, amino, amide, aryl, cycloalkyl,R⁶OC(O)—, R⁶C(O)O—, (R⁶)₂NC(O)O—, heterocyclyl, heteroaryl, orsulfonamide, wherein each of said alkoxy, amino, amide, aryl,cycloalkyl, heterocyclyl, heteroaryl, R⁶OC(O)—, R⁶C(O)O—, (R⁶)₂NC(O)O—,and sulfonamide is optionally substituted; and iii) when U is

and —Y—X is —(C₁₋₆)alkyl-X and X is aryl, then said (C₁₋₆)alkyl in —Y—Xis further optionally substituted by (C₁₋₃)alkyl, hydroxyl, halogen,(C₁₋₃)alkoxy, amide, amino, ((C₁₋₃)alkyl)amino, halo(C₁₋₃)alkyl, orhalo(C₁₋₃)alkoxy. 2-6. (canceled)
 7. The compound of claim 1, whereinsaid compound is of Formula II, or a pharmaceutically acceptable salt,solvate, hydrate, or diastereomer thereof:

Wherein m is 0, 1, 2, 3, 4, 5, or 6; —Y—X is selected from the groupconsisting of a) —O—(C₀₋₃)alkyl-X, which is optionally substituted; b)—(C₀₋₃)alkyl-S—X, which is optionally substituted; c) —S—(C₁₋₃)alkyl-X,which is optionally substituted; and d) —(C₁₋₆)alkyl-X, which isoptionally substituted; X is optionally-substituted aryl oroptionally-substituted heteroaryl; E is a bond or carbonyl; G is alkoxy,amino, amide, aryl, cycloalkyl, R⁶OC(O)—, R⁶C(O)O—, (R⁶)₂NC(O)O—,heterocyclyl, heteroaryl, or sulfonamide, wherein each of the alkoxy,amino, amide, aryl, cycloalkyl, heterocyclyl, heteroaryl, R⁶OC(O)—,R⁶C(O)O—, (R⁶)₂NC(O)O—, and sulfonamide is optionally substituted; R¹and R², each independently, are H, alkyl, amide, amino, cyano, alkoxy,hydroxyl, halogen, cycloalkyl, aryl, heteroaryl, or heterocyclyl,wherein each of the alkyl, alkoxy, amide, amino, cycloalkyl, aryl,heteroaryl, and heterocyclyl is optionally substituted; R³ and R⁴, eachindependently, are H, alkyl, alkoxy, amide, amino, R⁶OC(O)—, R⁶C(O)O—,cyano, cycloalkyl, heterocyclyl, hydroxyl, halogen, sulfonamide, ornitro, wherein each of said alkyl, alkoxy, amide, amino, R⁶OC(O)—,R⁶C(O)O—, cycloalkyl, heterocyclyl, and sulfonamide groups is optionallysubstituted; and R⁶, on each occurrence, independently is H, alkyl,aryl, cycloalkyl, heteroaryl, or heterocyclyl, wherein each of saidalkyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl is optionallysubstituted; Provided that when —Y—X is —O—CH₂—X, then X is furthersubstituted; and when —Y—X is —(C₁₋₆)alkyl-X and X is aryl, then said(C₁₋₆)alkyl in —Y—X is further optionally substituted by (C₁₋₃)alkyl,hydroxyl, halogen, (C₁₋₃)alkoxy, amide, amino, ((C₁₋₃)alkyl)amino,halo(C₁₋₃)alkyl, or (C₁₋₃)alkoxy.
 8. (canceled)
 9. The compound of claim1, wherein said compound is of Formula III, or a pharmaceuticallyacceptable salt, solvate, hydrate, or diastereomer thereof:

Wherein m is 0, 1, 2, 3, or 4; —Y—X is selected from the groupconsisting of a) —O—(C₀₋₃)alkyl-X, which is optionally substituted; b)—(C₀₋₃)alkyl-S—X, which is optionally substituted; and c)—S—(C₁₋₃)alkyl-X, which is optionally substituted; X isoptionally-substituted aryl or optionally-substituted heteroaryl; G isalkoxy, amino, amide, aryl, cycloalkyl, R⁶OC(O)—, R⁶C(O)O—,(R⁶)₂NC(O)O—, heterocyclyl, heteroaryl, or sulfonamide, wherein each ofthe alkoxy, amino, amide, aryl, cycloalkyl, heterocyclyl, heteroaryl,R⁶OC(O)—, R⁶C(O)O—, (R⁶)₂NC(O)O—, and sulfonamide is optionallysubstituted; R¹ and R², each independently, are H, alkyl, amide, amino,cyano, alkoxy, hydroxyl, halogen, cycloalkyl, aryl, heteroaryl, orheterocyclyl, wherein each of the alkyl, alkoxy, amide, amino,cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionallysubstituted; R³, each independently, is H, alkyl, alkoxy, amide, amino,R⁶OC(O)—, R⁶C(O)O—, cyano, cycloalkyl, heterocyclyl, hydroxyl, halogen,sulfonamide, or nitro, wherein each of said alkyl, alkoxy, amide, amino,R⁶OC(O)—, R⁶C(O)O—, cycloalkyl, heterocyclyl, and sulfonamide groups isoptionally substituted; and R⁶, on each occurrence, independently is H,alkyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, wherein each ofsaid alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl is optionallysubstituted; Provided that when —Y—X is —O—CH₂—X, X is furthersubstituted.
 10. (canceled)
 11. The compound of claim 1, wherein saidcompound is of Formula IV, or a pharmaceutically acceptable salt,solvate, hydrate, or diastereomer thereof:

Wherein m is 0, 1, 2, or 3; —Y—X is —O—(C₀₋₃)alkyl-X; X isoptionally-substituted aryl or optionally-substituted heteroaryl; R¹ andR², each independently, are H, optionally-substituted 3 to 7-memberedheterocyclyl, or optionally-substituted (C₁₋₆)alkyl; G is selected fromthe group consisting of alkoxy, amino, cycloalkyl, heterocyclyl, andheteroaryl, and i) when G is alkoxy, cycloalkyl, heterocyclyl, orheteroaryl, then each of the alkoxy, cycloalkyl, heterocyclyl, andheteroaryl is further optionally substituted by one or more substituentsindependently selected from the group consisting of: a)—(C₀₋₆)alkyl-C(O)N(R⁷)₂ optionally substituted by one or moresubstituents independently selected from the group consisting of(C₁₋₃)alkyl, —(C₀₋₃)alkyl-OH, (C₁₋₃)alkoxy, —(C₀₋₃)alkyl-C(O)OH,—(C₀₋₃)alkyl-S(O)₂NH₂, and —(C₀₋₃)alkyl-C(O)N(R⁷)₂; b) (C₁₋₆)alkyloptionally substituted by one or more substituents independentlyselected from the group consisting of hydroxyl, —NH₂, —(C₀₋₃)alkyl-OH,halogen, —(C₀₋₃)alkyl-C(O)OH, and —(C₀₋₃)alkyl-C(O)N(R⁷)₂; c)(C₁₋₆)alkoxy optionally substituted by one or more same or differenthalogens; d) —OH; e) ureido; f) halogen; g) —C(O)(C₁₋₆)alkyl; h)—C(O)O(C₁₋₆)alkyl; i) —S(O)₂(C₁₋₆)alkyl; and j) —S(O)₂N(R⁷)₂; ii) when Gis amino, said amino is further optionally substituted by one or twosubstituents independently selected from the group consisting of: 1)—(C₀₋₆)alkyl-C(O)N(R⁷)₂ optionally substituted by one or moresubstituents independently selected from the group consisting of(C₁₋₃)alkyl, —(C₀₋₃)alkyl-OH, (C₁₋₃)alkoxy, —(C₀₋₃)alkyl-C(O)OH,—(C₀₋₃)alkyl-S(O)₂NH₂, and —(C₀₋₃)alkyl-C(O)NH₂; 2) (C₁₋₆)alkyloptionally substituted by one or more substituents independentlyselected from the group consisting of (C₁₋₃)alkyl, hydroxyl, —NH₂,—(C₀₋₃)alkyl-OH, halogen, —(C₀₋₃)alkyl-C(O)OH, and—(C₀₋₃)alkyl-C(O)N(R⁷)₂; 3) —C(O)(C₁₋₆)alkyl; 4) —C(O)O(C₁₋₆)alkyl; and5) —S(O)₂(C₁₋₆)alkyl; R⁷, each independently, is H or (C₁₋₆)alkyl; R³ isH, (C₁₋₆)alkyl, (C₁₋₆)alkoxy, amide, amino, R⁶OC(O)—, R⁶C(O)O—, cyano,(C₃₋₇)cycloalkyl, 4- to 8-membered heterocyclyl, hydroxyl, halogen,sulfonamide, or nitro, wherein each of said (C₁₋₆)alkyl, (C₁₋₆)alkoxy,amide, amino, R⁶OC(O)—, R⁶C(O)O—, (C₃₋₇)cycloalkyl, 4- to 8-memberedheterocyclyl, and sulfonamide groups is optionally substituted; and R⁶,on each occurrence, independently is H, (C₁₋₆)alkyl, 6- to 10-memberedaryl, (C₃₋₇)cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 8-memberedheterocyclyl, wherein each of said (C₁₋₆)alkyl, said 6- to 10-memberedaryl, said (C₃₋₇)cycloalkyl, said 5- to 6-membered heteroaryl, and said4 to 8-membered heterocyclyl is optionally substituted; Provided thatwhen Y—X is —O—CH₂—X, then X is further substituted.
 12. The compound ofclaim 1, wherein —Y—X is —O—X or —O—(C₁₋₃)alkyl-X. 13-14. (canceled) 15.The compound of claim 1, wherein X is phenyl, pyridyl, or pyrimidyl,wherein each of said phenyl, pyridyl, and pyrimidyl is optionallysubstituted.
 16. The compound of claim 1, wherein X is phenyl that isoptionally substituted by one to three substituents independentlyselected from the group consisting of halogen, haloalkyl, haloalkoxy,(alkyl)amino, amino, and (dialkyl)amino.
 17. The compound of claim 1,wherein said compound is of Formula V, or a pharmaceutically acceptablesalt, solvate, hydrate, or diastereomer thereof:

Wherein Y is —O— or O—CH₂—; m is 0, 1, or 2; M is halogen, haloalkyl,haloalkoxy, (alkyl)amino, amino, or (dialkyl)amino; R¹ and R², eachindependently, are H or (C₁₋₃)alkyl; R³ is H, (C₁₋₃)alkyl, (C₁₋₃)alkoxy,amino, hydroxyl, or halogen; G is selected from the group consisting ofi) amino optionally substituted by 1) —(C₀₋₃)alkyl-C(O)N(R⁷)₂ furtheroptionally substituted by one or more substituents independentlyselected from the group consisting of (C₁₋₃)alkyl, —(C₀₋₃)alkyl-OH,—(C₁₋₃)alkoxy, —(C₀₋₃)alkyl-C(O)OH, —(C₀₋₃)alkyl-S(O)₂NH₂, and—(C₀₋₃)alkyl-C(O)NH₂; 2) (C₁₋₃)alkyl optionally substituted by one ormore substituents independently selected from the group consisting of(C₁₋₃)alkyl, hydroxyl, —NH₂, —(C₀₋₃)alkyl-OH, halogen,—(C₀₋₃)alkyl-C(O)OH, and —(C₀₋₃)alkyl-C(O)N(R⁷)₂; 3) —C(O)O(C₁₋₃)alkyl;or 4) —C(O)(C₁₋₃)alkyl; ii) 3 to 7-membered heterocyclyl optionallysubstituted by one or more substituents independently selected from thegroup consisting of a) —(C₀₋₃)alkyl-C(O)N(R⁷)₂ further optionallysubstituted by one or more substituents independently selected from thegroup consisting of (C₁₋₃)alkyl, —(C₀₋₃)alkyl-OH, —(C₁₋₃) alkoxy,—(C₀₋₃)alkyl-C(O)OH, —(C₀₋₃)alkyl-S(O)₂NH₂, and —(C₀₋₃)alkyl-C(O)NH₂; b)(C₁₋₃)alkyl optionally substituted by one or more substituentsindependently selected from the group consisting of (C₁₋₃)alkyl,hydroxyl, —NH₂, —(C₀₋₃)alkyl-OH, halogen, —(C₀₋₃)alkyl-C(O)OH, and—(C₀₋₃)alkyl-C(O)N(R⁷)₂; c) (C₁₋₃)alkoxy optionally substituted by oneor more same or different halogens; d) halogen; e) —S(O)₂(C₁₋₃)alkyl; f)—C(O)O(C₁₋₃)alkyl; and g) —C(O)(C₁₋₃)alkyl; and, iii) 5- to 6-memberedheteroaryl optionally substituted by one or more substituentsindependently selected from the group consisting of the a)-g) moietiesas above defined; and, R⁷ independently is H or (C₁₋₃)alkyl.
 18. Thecompound of claim 17, wherein Y is —O—.
 19. The compound of claim 17,wherein M is halogen or haloalkyl.
 20. (canceled)
 21. The compound ofclaim 1, wherein one of R¹ and R² is H, and the other is (C₁₋₃)alkyl.22-23. (canceled)
 24. The compound of claim 1, wherein G is a 5- or6-membered heterocyclyl group selected from the group consisting of:

wherein R⁹ is H, —(C₁₋₃)alkyl-C(O)NH₂, —C(₁₋₃)alkyl-C(O)N((C₁₋₃)alkyl)₂,—C(O)OH, —C(O)NH₂, —C(O)(C₁₋₃)alkyl, —C(O)O(C₁₋₄)alkyl,—S(O)₂(C₁₋₃)alkyl, (C₁₋₃)alkyl, or halogen. 25-26. (canceled)
 27. Thecompound of claim 1, wherein G is 5- to 6-membered heteroaryl selectedfrom the group consisting of:

wherein R¹⁰ is H, (C₁₋₃)alkyl, —(C₁₋₃)alkyl-C(O)NH₂, or —C(O)NH₂; andR¹¹ is H, halogen, (C₁₋₃)alkyl, halo(C₁₋₃)alkoxy, or halo(C₁₋₃)alkyl.28. (canceled)
 29. The compound of claim 1, wherein G is

and R⁸ is H, (C₁₋₃)alkyl, —(C₁₋₃)alkyl-OH, —(C₁₋₃)alkyl-C(O)OH, or—(C₁₋₃)alkyl-C(O)N(R⁷)₂.
 30. The compound of claim 29, wherein G isselected from the group consisting of:


31. (canceled)
 32. The compound of claim 1, wherein said compound isselected from the group consisting of:1-(4-(4-Fluorophenoxy)phenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole(Compound 9);2-(4-Chloro-1-methyl-1H-pyrazol-3-yl)-1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazole(Compound 10);1-(4-(4-fluorophenoxy)phenyl)-2-(1H-imidazol-4-yl)-1H-benzo[d]imidazole(Compound 11);(S)-5-(1-(4-(4-Fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one(Compound 14);2-((1H-tetrazol-5-yl)methyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazole(Compound 15);1-(4-(4-Fluorophenoxy)phenyl)-2-((5-methyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole(Compound 16);1-(4-(4-Fluorophenoxy)phenyl)-2-(2-(piperidin-1-yl)ethyl)-1H-benzo[d]imidazole(Compound 17); tert-Butyl(S)-2-(1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (Compound 18); tert-Butyl4-(1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate(Compound 19);1-(4-(4-Fluorophenoxy)phenyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole(Compound 20);(S)-1-(4-(4-Fluorophenoxy)phenyl)-2-(pyrrolidin-2-yl)-1H-benzo[d]imidazole(Compound 21);2-(4-(1-(4-(4-Fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)acetamide(Compound 23);N,N-diethyl-2-(4-(1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)acetamide(Compound 24);(S)-2-(2-(1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)acetamide(Compound 25);2-(((1-(4-(4-(Trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)amino)acetamide(Compound 26);2-((1-(1-(4-(4-(Trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)acetamide(Compound 27);2-((1-(1-(4-(4-(Trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)propanamide(Compound 28);2-(((1-(4-(4-(Trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)amino)propanamide(Compound 29);3-Hydroxy-2-(((1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)amino)propanamide(Compound 30);3-Hydroxy-2-((1-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)propanamide(Compound 31);1-(1-(1-(4-(4-(Trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethyl)pyrrolidine-2-carboxamide(Compound 32);1-((1-(4-(4-(Trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)pyrrolidine-2-carboxamide(Compound 33);5-Amino-5-oxo-4-((1-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)pentanoicacid (Compound 34);2-((1-(1-(4-(4-(Trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)pentanediamide(Compound 35);2-(((1-(4-(4-(Trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)amino)pentanediamide(Compound 36);5-Amino-5-oxo-4-(((1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)amino)pentanoicacid (Compound 37);1-(4-(4-Fluorophenoxy)phenyl)-2-((1-methyl-1H-tetrazol-5-yl)methyl)-1H-benzo[d]imidazole(Compound 38);1-(5-((1-(4-(4-Fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)-1H-tetrazol-1-yl)ethan-1-one(Compound 39);1-(4-(4-Fluorophenoxy)phenyl)-2-((1-(methylsulfonyl)-1H-tetrazol-5-yl)methyl)-1H-benzo[d]imidazole(Compound 40);5-((1-(4-(4-Fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)-N-methyl-1H-tetrazole-1-carboxamide(Compound 41);5-Oxo-1-((1-(4-(4-(trifluoro-methyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)-pyrrolidine-2-carboxylicacid (Compound 42); and5-Oxo-1-((1-(4-(4-(trifluoro-methyl)phenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)methyl)-pyrrolidine-2-carboxamide(Compound 43), and pharmaceutically acceptable salts, solvates,hydrates, and diastereomers thereof. 33-34. (canceled)
 35. Apharmaceutical composition comprising the compound of claim 1 and apharmaceutically acceptable carrier or diluent.
 36. A method of treatinga disorder responsive to blockade of sodium channels in a mammalsuffering from said disorder, comprising administering to a mammal inneed of such treatment an effective amount of a compound of claim 1.37-38. (canceled)
 39. The method of claim 36, wherein said disorder isresponsive to blockade of Na_(v)1.7 sodium channels.
 40. A method fortreating a disorder or providing local anesthesia in a mammal identifiedas in need thereof, comprising administering to said mammal an effectiveamount of a compound of claim 1, wherein said disorder is selected fromthe group consisting of stroke, neuronal damage resulting from headtrauma, epilepsy, seizures, neuronal loss following global and focalischemia, pain, migraine, primary erythromelalgia, paroxysmal extremepain disorder, cerebellar atrophy, ataxia, mental retardation, aneurodegenerative disorder, manic depression, tinnitus, myotonia, amovement disorder, and cardiac arrhythmia.
 41. The method of claim 40,wherein said method is for treating pain. 42-43. (canceled)
 44. A methodof modulating Nav1.7 sodium channel in a mammal, comprisingadministering to the mammal at least one compound of claim
 1. 45-57.(canceled)